extreme phenotypic diversity and nonpenetrance in families with the lmna gene mutation r644c

� 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:1530–1542 (2008)

Extreme Phenotypic Diversity and Nonpenetrancein Families With the LMNA Gene Mutation R644C

Julia Rankin,1* Michaela Auer-Grumbach,2 Warwick Bagg,3 Kevin Colclough,4

Nguyen Thuy Duong,5 Jane Fenton-May,6 Andrew Hattersley,7 Judith Hudson,8 Philip Jardine,9

Dragana Josifova,10 Cheryl Longman,11,12 Robert McWilliam,13 Katharine Owen,14

Mark Walker,15 Manfred Wehnert,5 and Sian Ellard4,7

1Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK2Institute of Human genetics and Department of Internal Medicine, Medical Research Centre, Medical University of Graz, Austria

3Department of Medicine, University of Auckland, Auckland, New Zealand4Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK

5Institute of Human Genetics, Ernst-Moritz-Arndt University, Greifswald, Germany6Institute of Medical Genetics, Cardiff and Vale NHS Trust, Cardiff, UK

7Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK8Northern Genetics Service, Newcastle upon Tyne, UK

9Bristol Hospital for Sick Children, Bristol, UK10Department of Clinical Genetics, Guys and St Thomas NHS Trust, London, UK

11Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK12Clinical Genetics Department, Molecular Medicine Centre, Western General Hospital, Edinburgh, UK

13Fraser of Allander Neurosciences Unit, Yorkhill NHS Trust, Glasgow, UK14Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

15School of Clinical Medical Sciences, Medical School, Newcastle University, Newcastle upon Tyne, UK

Received 28 April 2007; Accepted 6 March 2008

Mutations in the LMNA gene result in diverse phenotypesincluding Emery Dreifuss muscular dystrophy, limb girdlemuscular dystrophy, dilated cardiomyopathy with conduc-tion system disease, Dunnigan type familial partial lipodys-trophy, mandibulo acral dysplasia, Hutchinson Gilfordprogeria syndrome, restrictive dermopathy and autosomalrecessive Charcot Marie Tooth type 2. The c.1930C>T(R644C) missense mutation has previously been reported ineight unrelated patients with variable features includingleft ventricular hypertrophy, limb girdle muscle weakness,dilated cardiomyopathy and atypical progeria. Here wereport on the details of nine additional patients in eightfamilies with this mutation. Patients 1 and 2 presentedwith lipodystrophy and insulin resistance, Patient 1 havingin addition focal segmental glomerulosclerosis. Patient 3

presented with motor neuropathy, Patient 4 with arthro-gryposis and dilated cardiomyopathy with left ventricularnon-compaction, Patient 5 with severe scoliosis and con-tractures, Patient 6 with limb girdle weakness and Patient 7with hepatic steatosis and insulin resistance. Patients 8 and9 are brothers with proximal weakness and contractures.Nonpenetrance was observed frequently in first degreerelatives. This report provides further evidence of theextreme phenotypic diversity and low penetrance associatedwith the R644C mutation. Possible explanations for theseobservations are discussed. � 2008 Wiley-Liss, Inc.

Key words: LMNA gene; lamin A; lamin C; lamin A/C;laminopathy

How to cite this article: Rankin J, Auer-GrumbachM, BaggW, ColcloughK, DuongNT, Fenton-May J, HattersleyA, Hudson J, Jardine P, Josifova D, Longman C, McWilliam R, Owen K, Walker M, Wehnert M, Ellard S. 2008.

Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutationR644C. Am J Med Genet Part A 146A:1530–1542.

INTRODUCTION

The LMNA gene encodes the proteins lamin Aand lamin C which are major components of thenuclear lamina. The phenotypes caused by muta-tions in the LMNA gene include Emery Dreifussmuscular dystrophy (EDMD), limb girdle musculardystrophy (LGMD1B), dilated cardiomyopathy with

*Correspondence to: Dr. Julia Rankin, Department of Clinical Genetics,Royal Devon and Exeter NHS Foundation Trust, Gladstone Road, ExeterEX1 2ED, UK. E-mail: [email protected]

DOI 10.1002/ajmg.a.32331

conduction system disease (DCM-CSD), Dunnigantype familial partial lipodystrophy (FPLD), mandi-bulo acral dysplasia (MAD), Hutchinson Gilfordprogeria syndrome (HGPS), restrictive dermopathy(RD) and autosomal recessive Charcot MarieTooth type 2 (CMT2B1) [reviewed by Rankin andEllard, 2006]. Collectively these are termed ‘lamino-pathies’ and are striking in their diversity. Whilethese phenotypes are clearly separate entities, thereis considerable overlap between them with, forexample, some FPLD patients having skeletal andcardiac muscle involvement [Vantyghem et al., 2004].In addition, there are numerous reports of patientswho harbor a LMNAmutation but whose phenotype,while including features of one or more lamino-pathy, cannot clearly be assigned to one group [Cauxet al., 2003; Young et al., 2005; Van Esch et al., 2006].

Small deletions and splicing mutations have beenreported but the majority of LMNA mutationsare predicted to result in missense changes affectingconserved residues [Rankin and Ellard, 2006].The genotype phenotype relationship is complexas for some phenotypes and mutations there is aclear correlation whereas for others there is not. Forexample, most patients with FPLD carry a missensechange of codon 482 [Cao and Hegele, 2000;Shackleton et al., 2000] butmutations causingEDMD,LGMD1B and DCM-CSD are found throughout thegene.

While many mutations are highly penetrant, forexample the c.1824C>T splicing mutation found inmost typical HGPS patients [De Sandre-Giovannoliet al., 2003; Eriksson et al., 2003], others such asR401C exhibit nonpenetrance [Vytopil et al., 2002].Some LMNA mutations are associated with a veryvariable phenotype. For example, members of thesame family carrying a single nucleotide deletion inexon 6 had either pure DCM-CSD, EDMD or LGMD[Brodsky et al., 2000] and the missense change E358Khas been detected in unrelated patients with typicalEDMD, with congenital axial weakness and withmuscle weakness in combination with features oflipodystrophy [Mercuri et al., 2004]. One particularmissense change, c.1930C>T (R644C), has beenassociated with strikingly diverse phenotypes havingbeen reported in unrelated patients with left ventri-cular hypertrophy, limb girdle muscle weakness,dilated cardiomyopathy [Genschel and Schmidt,2000; Mercuri et al., 2005] and atypical progeria[Csoka et al., 2004]. Lack of segregation with pheno-type as well as nonpenetrance in relatives raisedthe possibility that this missense change may be arare polymorphism. However, there is strong evi-dence in support of its pathogenicity. Firstly, theR644C missense change has not been detected in1,500 normal chromosomes [Muntoni et al., 2006;and authors own data] whereas it has been detectedin at least 17 patients with features of laminopathy[Genschel and Schmidt, 2000; Csoka et al., 2004;

Mercuri et al., 2005; Muntoni et al., 2006; and patientsreported here]. Secondly, the arginine residue atposition 644 is highly conserved across severalspecies. Here we report in detail on the clinicalfeatures of nine patients harboring the R644C mis-sense mutation, demonstrating nonpenetrance intheir relatives and an even wider spectrum ofphenotypic diversity than previously recognized.

METHODS

Genomic DNA was extracted from peripherallymphocytes using standard procedures. In allpatients the 12 exons and exon–intron junctionsof the LMNA gene were amplified by PCR in 11 frag-ments. For Patients 1, 2 and 8 the ten exons andexon–intron junctions of the ZMPSTE24 gene wereamplified in 10 fragments. The PCR primers used forLMNA and ZMPSTE24 amplification are availableupon request. PCR products were sequenced usingstandard methods on an ABI 3100 or ABI 3730(Applied Biosystems, Warrington, UK). Sequenceswere compared to the published sequences (LMNA:NM_005572.2; ZMPSTE24: NM_005857.2) using Sta-den Analysis (http://staden. sourceforge.net/) orMutation Surveyor v.2.61 (http://biogene.com).Mutations were tested for co-segregation with thephenotype in other family members.

CLINICAL REPORTS

Patient 1

A 30-year-old female presented with a history ofthirst and polyuria. Diabetes mellitus was diagnosedand treated for 3 years with diet and oral hypo-glycemic agents. Insulinwas subsequently introducedand at clinical review aged 41, there was evidenceof severe insulin resistance (insulin requirement2.5 units/kg; normal 0.7–1 units/kg) as well ashypertension (166/99 mmHg) and dyslipidemia(cholesterol 9.1 mmol/L; normal range 3.7–5.2 mmol/l, HDL-cholesterol 2.83 mmol/L; normalrange 1.16–1.68 mmol/L, LDL-cholesterol 5.39; nor-mal 3.9–4.9 mmol/L and triglycerides 2.33 mmol/L;normal range 0.84–1.94 mmol/L). Oligomenorrhoeaand hirsutism had developed at the age of 40 years.On examination at age 41 there was acanthosisnigricans in the axillae and cervical regions (Fig. 1).Fat distribution was abnormal with decreased sub-cutaneous fat on the legs and gluteal region,central obesity and submandibular fat accumulation.Upper limb and subscapular skin fold thicknessmeasurements were normal (biceps 13.2 mm; normal7.4–16.7 mm, triceps 17.2mm; normal 14.4–28.2 mm,subscapular 25.3 mm; normal 13.4–30.1 mm, sup-railiac 21.5 mm; normal 6–25 mm and waist circum-ference82 cm) lower limbandchin skin fold thicknessmeasurements are not available. The age of onset of

PATIENTS WITH LMNA MUTATION R644C 1531

American Journal of Medical Genetics Part A

altered fat distribution is unknown. Body mass indexwas 25. There was also a past history of proteinuriasince age 24 (predating the diagnosis of diabetes) andrenal biopsy at age 32 showed focal segmentalglomerulosclerosis without evidence of diabeticnephropathy.

Echocardiography showed early concentric leftventricular hypertrophy, in keeping with her historyof hypertension, but no evidence of dilated cardio-myopathy. Electrocardiogram (ECG) was normal.Her father had died unexpectedly of a myocardialinfarct at age 43. He was not known to have diabetesor lipodystrophy but was described as ‘muscular’.Her mother had late onset diabetes but was notreported to have lipodystrophy. A heterozygousc.1930C>T (R644C) mutation in the LMNA gene wasfound in the proposita but parental samples wereunavailable (Fig. 5A).

Patient 2

At age 20 years a female was diagnosed with type 2diabetes mellitus having had symptoms of hyper-glycemia for several months. Insulin resistancesubsequently developed (insulin requirement byage 32 were 3 units/kg; normal 0.7–1 units/kg).Mild dyslipidemia was present (total cholesterol

5.8 mmol/l; normal range 3.7–5.2 mmol/l, HDL-cholesterol 0.9 mmol/l; normal range 1.16–1.68 mmol/L, LDL-cholesterol 4.1 mmol/l; normal3.9–4.9 mmol/L and triglycerides 1.9 mmol/l normalrange 0.84–1.94 mmol/L) and testosterone levelswere towards the upper limit of normal at 2.6 nmol/l(normal range in females 0.22–2.9 nmol/L).Menstruation had been regular since menarche atage 11 years.

Examination at age 20 revealed marked reductionof subcutaneous fat on the limbs (skin fold thicknessover biceps 1.5 mm; normal 7.4–16.7 mm and triceps2 mm; normal 14.4–28.2 mm) but fat was normallydistributed elsewhere (Fig. 2). The exact age of onsetof lipodystrophy was unclear. Lentigines and atyp-ical nevi were present on the limbs and trunk withincreased facial hair and male pattern abdominalhair. Acanthosis nigricans was absent. There wasmicrognathia and height was between the first andthird centiles (while the parents were reported tobe above average height), head circumference wasjust above the second centile and hand and fingerlength below the third centile. Abdominal sonogramshowed no evidence of polycystic ovaries butmultiple uterine fibroids were seen. Bilateral mildto moderate sensorineural hearing loss developedage 25 and magnetic resonance imaging (MRI) of the

FIG. 1. Patient 1: submandibular fat accumulation (A–C), acanthosis nigricans in axilla (C), reduced subcutaneous fat on the legs (D). [Color figure can be viewed inthe online issue, which is available at www.interscience.wiley.com.]

1532 RANKIN ET AL.


internal auditory meati revealed no abnormality. Anechocardiogram was normal. ECG showed restingtachycardia of 92beats/minbutwas otherwisewithinnormal limits. The presence of both deafness anddiabetes prompted testing for the mitochondrialmutation m.3243A>G in the patient’s lymphocyteDNA but this was absent. At review aged 34 thepatient was described as having an aged appear-ance (further clinical photographs unavailable). Herparents and sister had normal clinical examinationbut did not attend for ECG or echocardiogram. Theheterozygous LMNA mutation R644C was found inthe proband and in her unaffected mother (Fig. 5B).

Patient 3

An 8-year-old boy presented with progressivedifficulty walking and writing with episodic pain inthe feet and axilla. Examination revealed wasting ofthe intrinsic hand muscles and peroneal muscles,right pes cavus, bilateral foot drop with brisk lowerlimb reflexes and increased tone at the ankles but noother neurological abnormality. Neurophysiology

showed attenuation of motor responses in bothlower limbs and right upper limbandwas interpretedas being consistent with anterior horn cell disease ordistal motor neuropathy. MRI of the brain and spinalcord, echocardiogram and electrocardiogram (ECG)were normal. Muscle biopsy revealed neurogenicchanges only. Other routine investigations includingcreatine kinase (CK), very long chain fatty acids andgenetic testing for Spinal Muscular Atrophy (SMA)were also normal. LMNA mutation analysis revealedthe heterozygous R644C mutation in the probandand subsequently in the unaffected father (Fig. 5C).

Patient 4

A female baby with arthrogryposis was born after apregnancy complicated by first trimester bleedingand third trimester polyhydramnios. Contracturesaffected the elbows and hands and there wasbilateral club foot. Echocardiography in the neonatalperiod revealed a ventricular septal defect (VSD)and abdominal ultrasound a unilateral multicysticdysplastic kidney. There were dysmorphic features

FIG. 2. Patient 2: micrognathia (A, B), lentigines and reduced subcutaneous fat on the arms (C). [Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]



including prominent forehead, deep set eyes, flatnasal bridge, long philtrum and a high arched palate(clinical photograph unavailable). Primary dentitionwas absent. Motor development was delayed withsitting at 11 months but cognitive developmentwas normal. At 2 years the VSD had closed sponta-neously but echocardiography showed dilated car-diomyopathy with left ventricular non-compaction.Investigations including blood chromosome analysiswith testing for subtelomeric rearrangements anda 22q11 microdeletion, genetic testing for SMAand Myotonic Dystrophy and cranial MRI were allnormal. Nonspecific changes were seen on musclebiopsy. The heterozygous R644C mutation wasdetected on LMNA sequencing and subsequentlyfound to be present in the unaffected motherand maternal grandmother (Fig. 5D). A full cardiacassessment of both parents, including ECG andechocardiogram, was normal. A full neurologicalexamination of the mother was normal. Thematernal grandmother is reported to have diabetesand obesity and to have suffered a myocardialinfarct in her 30s. She subsequently developedmultiple sclerosis. She has declined further clinicalassessment.

Patient 5

A 13-year-old female presented with rapidly pro-gressive scoliosis and a past history of intermittent toewalking since age seven. Bilateral Achilles tendoncontractureshadbeen treated at age 9 yearswith serialplastering, followed by splinting for 2 years. Shefirst walked at 21 months but other developmentalmilestones were within normal limits. Examination atage 13 revealed right thoraco-lumbar scoliosis, spinalrigidity and mild bilateral contractures of the hams-trings, elbows and Achilles but with no evidence ofmuscle weakness or atrophy (Fig. 3). The scoliosisprogressed, requiring spinal fixation and subsequentreview at age 17 years revealed mild neck flexorweakness but no evidence of generalized weakness.CK levels, muscle MRI and nerve conduction studieswere normal, muscle biopsy showed occasionalatrophic fibers and normal routine immunostaining.Pulmonary function testing showed a mild restrictivedefect and echocardiography and ECG (including24 hr ECG) were normal. The heterozygous R644CLMNAmutation was detected in the patient and in herunaffected half-sister, her mother and her maternalgrandfather (Fig. 5E). Full clinical assessment of themother revealed nomuscleweakness, contractures orlipodystrophy and ECG and echocardiogram werenormal. A full brother had died aged 3 months from acongenital malformation syndrome caused by anunrelated de novo chromosomal rearrangement.

Patient 6

A 61-year-old male presented with a 7-year historyof progressive difficulty climbing stairs and rising

from a chair. Diabetes and hypertension had beendiagnosed aged 50 and were controlled with diet andantihypertensive agents, respectively. Examinationrevealed contractures of the elbows and postcervicalmuscles, weakness of limb girdle muscles, wingingof scapulae and wasting of humeral muscles (Fig. 4).There was no facial weakness. CK was normal,electromyography showed features of myopathy,muscle biopsy showed only nonspecific findings(emerin staining was normal). Echocardiographyand ECG were normal. Limb girdle weaknessprompted testing for facioscapulohumeral musculardystrophy (FSHD) which revealed a borderline frag-ment of 37 kilobases (kb). His sister was reportedto have similar problems but had been given adiagnosis of CMT. She had a cardiac pacemaker forheart block and her son was reported to have limb

FIG. 3. Patient 5 aged 15 years: right thoraco-lumbar scoliosis prior tosurgical treatment. Tendoachilles contractures had been treated at the time ofthe photograph. [Color figure can be viewed in the online issue, which isavailable at www.interscience.wiley.com.]

1534 RANKIN ET AL.


girdle weakness (Fig. 5F). Neither of these relativeswished to attend for assessment. The patient’smother was said not to have similar problems andhis father had died in the Second World War. Theheterozygous R644C LMNA mutation was present inthe patient but samples from other relatives were notavailable.

Patient 7

A 34-year-old male presented with non-alcoholichepatic steatosis. He was overweight with centraladiposity but no frank partial lipodystrophy (skinfold thickness measurements; triceps 21.8 mm;normal 6.7–16.5 mm, biceps 9.8 mm; normal 4.1–10.1 mm, subscapular 32.7 mm; normal 11–26.3 mm,suprailiac 36.1 mm; normal 16.3–36.9 mm, waistcircumference 116 cm). Hypertension, hypercho-lesterolemia and mild insulin resistance (fastinginsulin 16 mU/L; normal <15 mU/L) were detectedbut the patient was not diabetic. Echocardiographywas normal but the patient did not attend for an ECG.There was no evidence of myopathy. There was apaternal family history of ischemic heart disease butnot of features of laminopathy. The heterozygousR644C LMNA mutation was present in the patientbut parental samples were not available for testing(Fig. 5G).

Patients 8 and 9

An adult male (Patient 8) had a history ofprogressive weakness with frequent falls since age

10 years. On examination he had marked proximalmuscle weakness and wasting with contractures ofthe spine, elbows and Achilles tendons and waswheelchair bound having lost ambulation aged 26.CK was 281 U/L (normal <171 U/L) and echocardio-gram and ECG were normal. A muscle biopsy show-ed severe myopathic changes with normal routineimmunostaining including emerin. The patient’sbrother (Patient 9; Fig. 5H) presented with a similarhistory since age 33 years. Examination revealedmarked weakness of proximal upper and lowerlimbs with contractures of the elbows, spine andAchilles tendons. ECG and echocardiogram werenormal, CK level is not available and muscle biopsywas not done. A third brother had a different clinicalpresentation with club feet at birth and subsequentdistal lower limb weakness. Nerve conductionstudies in him showed an axonal sensorimotorneuropathy. A fourth sibling, the parents and themother’s sibling were asymptomatic with normalneurological examinations. CK levels were mildlyelevated in the unaffected sibling (240 U/L) andmother (412 U/L). Mutation analysis of the STA geneencoding emerin revealed no abnormality in Patient8, however the heterozygous R644C LMNA mutationwas detected in both patients and in their healthysibling, mother and mother’s sibling but not in thebrother with neuropathy (Fig. 5H). The healthyrelatives have been offered cardiac assessment buthave so far declined.

DISCUSSION

The patients reported here have very diversephenotypes but all harbor the same LMNA missensechange, c.1930C>T, predicted to result in the sub-stitution of arginine by cysteine at codon 644(R644C). All patients had some features of laminop-athy but some had additional, previously unreportedcomplications (Table I). Patient 1 has clinical featuresconsistent with FPLD and in addition has renaldisease with focal segmental glomerulosclerosis(FSGS). Proteinuric renal disease appears to be afrequent observation in those with various forms oflipodystrophy, with reported histologies of bothFSGS and mesangiocapillary glomerulonephritistype 2 [Javor et al., 2004; Owen et al., 2004], althoughthe mechanism is unknown. In addition, FSGShas been found in patients with MAD owing toZMPSTE24 deficiency [Agarwal et al., 2006] which isconsidered to cause a secondary laminopathy (seebelow). Patient 2 has atypical lipodystrophy, lackingfacial fat accumulation, but with additional featuresincluding mild growth retardation, micrognathia andsensorineural hearing loss. More marked growthretardation and micrognathia are seen in MAD butsensorineural hearing loss has not been reported as afeature of laminopathy. A prematurely aged appea-rance developed in this patient at age 33 and this

FIG. 4. Patient 6: elbow contractures and biceps wasting. ‘Round shoul-dered’ appearance consistent with shoulder girdle weakness. [Color figurecan be viewed in the online issue, which is available at www.interscience.wiley.com.]



feature has been reported in many patients withlaminopathy [reviewed by Rankin and Ellard, 2006].Interestingly, a previously reported patient with thesame mutation was described as having ‘atypicalprogeria’ with short stature, generalized wastingand thinned skin [Csoka et al., 2004] and so hassimilarities to our patient. Patient 3 has anteriorhorn cell disease or distal motor neuropathy withpyramidal signs. Recessive LMNA mutations havebeen found in a number of consanguineous Algerianand Moroccan families with CMT2, an axonal motorand sensory neuropathy [Tazir et al., 2004], and inthese motor symptoms usually precede sensorysymptoms. In addition, some patients with hetero-

zygous LMNA mutations have evidence of neuro-pathy, usually in addition to myopathy [Goizet et al.,2004; Benedetti et al., 2005; Walter et al., 2005].However upper motor neuron involvement, andindeed central nervous system involvement, is nota recognized feature of the known laminopathysyndromes. Congenital contractures with club foot,as found in Patient 4, have been reported in otherpatients with EDMD due to heterozygous LMNAmutations [Bonne et al., 2000] and the dilatedcardiomyopathy found in this patient would alsobe consistent albeit presenting at a younger agethan usual. However the dysmorphic featuresand congenital heart defect (VSD) would not be

FIG. 5. Family trees of Patients 1 (A), 2 (B), 3 (C), 4 (D), 5 (E), 6 (F), 7 (G), 8 and 9 (H). Patients are marked with an arrow. Numbers within small parentheses denotenumbers of siblings.

1536 RANKIN ET AL.


consistent and so a second diagnosis might bepresent. The pattern of contractures in Patient 5 isconsistent with a diagnosis of EDMD and otherpatients with autosomal dominant EDMD have hadsevere scoliosis [Bonne et al., 2000]. Limb girdleweakness with elbow and post cervical contracturesfound in Patient 6 is consistent with the EDMDphenotype although lack of cardiac involvement atage 61 is unusual. Interestingly, molecular genetictesting for FSHD in this patient gave an abnormalresult (see below). Patients 8 and 9 also presented

with proximal muscle weakness and contracturesof the elbows, Achilles and spine. Although thedistribution of muscle weakness at presentation inautosomal dominant EDMD is typically humer-operoneal, the combination of proximal weaknessand contractures has been reported in several EDMDpatients with LMNA mutations [Bonne et al., 2000].Interestingly, another patient heterozygous for theR644C mutation was reported to have severe EDMD[Muntoni et al., 2006]. Hepatic steatosis, as reportedin Patient 7, is a recognized feature of FPLD due to

FIG. 5. (Continued )



TABLE

I.Clinic

alFeat

ure

sofPat

ients

and

Rela

tives

Har

boring

the

R644C

Muta

tion

inLM

NA

Pat

ientID

Sex

Age

atdia

gnosi

s(y

ear

s)Clinic

alfe

ature

sRela

tives

with

R644C

Clinic

alfe

ature

sin

rela

tive

Evid

ence

ofad

ditio

nal

etiolo

gic

aldia

gnosi

sin

pat

ient/

rela

tive

Pat

ient1

F30

Insu

lin

resi

stan

cePar

enta

lsa

mple

sunav

aila

ble

No

Dia

bete

sD

ysl

ipid

em

iaLi

podyst

rophy

Foca

lse

gm

enta

lglo

meru

losc

lero

sis

Hypertensi

on

Pat

ient2

F20

Insu

lin

resi

stan

ceM

oth

er

None

No

Dia

bete

sH

ypera

ndro

genis

mLi

podyst

rophy

Dysl

ipid

em

iaM

ild

short

stat

ure

Lentigin

es

Pre

mat

ure

agein

gSe

nso

rineura

lhear

ing

loss

U

Pat

ient3

M8

Dis

talm

oto

rneuro

pat

hy

Fat

her

None

No

Pyra

mid

alsi

gnsU

Pat

ient4

F2

Arthro

gry

posi

sVSD

U

Dysm

orp

his

mAbse

ntprim

ary

dentition

U

Multic

yst

icdysp

last

ickid

ney

U

Dilat

ed

card

iom

yopat

hy

and

left

ventric

ula

rnon-c

om

pac

tion

Moth

er

None.

Ech

oca

rdio

gra

man

dECG

norm

al

No

butdysm

orp

his

man

dVSD

may

suggest

additio

nal

dia

gnosi

s

Mat

ern

algra

ndm

oth

er

Multip

lesc

lero

sis

Myo

card

ialin

farc

tag

e30

(reported

by

fam

ily

but

unco

nfirm

ed)

Pat

ient5

F13

Rap

idly

pro

gre

ssiv

esc

oliosi

sSp

inal

rigid

ity

Ham

string,elb

ow

and

Ach

ille

sco

ntrac

ture

s

Moth

er

Sist

er

None

Ech

oca

rdio

gra

man

dECG

norm

alN

one

No

Pat

ient6

M61

Lim

bgirdle

weak

nes

s,m

ild

contrac

ture

sPar

enta

l/fa

mily

sam

ple

sunav

aila

ble

Bord

erline

frag

mentFSH

D

Dia

bete

s

Pat

ient7

M34

Hepat

icst

eat

osi

sPar

enta

lsa

mple

sunav

aila

ble

Insu

lin

resi

stan

ceH

ypertensi

on

Dysl

ipid

em

iaPat

ients

8an

d9

M10

and

33

Pro

xim

allim

bw

eak

nes

sw

ith

contrac

ture

sH

eal

thy

sibling,m

oth

eran

dm

oth

er’s

sibling

None

Neuro

pat

hy

inbro

ther

NO

Tca

rryin

gR644C


Publish

ed

pat

ients

Gensc

helan

dSc

hm

idt[2

000]

Not

reported

Notre

ported

Dilat

ed

card

iom

yopat

hy

Notre

ported

Notre

ported

Cso

ka

etal

.[2

004]

M20

Aty

pic

alpro

geria

Notre

ported

Notre

ported

Mer

curi

etal

.[2

005]

case

2(f

urther

deta

ils

publish

ed

by

Munto

nietal

.,2006)

M8

Sever

ehypertro

phic

card

iom

yopat

hy

Fat

her

(moth

erhad

hypertro

phic

card

iom

yopat

hy)

Mild,su

bcl

inic

alpar

aspin

alan

dbic

eps

involv

em

ent

on

MRI

Ech

oca

rdio

gra

man

dECG

norm

al

Feat

ure

sofm

yofibrillar

myopat

hy,

desm

inm

uta

tion

Mer

curi

etal

.[2

005]

case

3F

57

Atria

lfibrillat

ion

Mild

pro

xim

allim

bw

eak

nes

sN

otre

ported

Notre

ported

Mer

curi

etal

.[2

005]

case

4M

9M

oto

rdela

yLi

gam

ento

us

laxity

Fat

her

(moth

erhad

card

iom

yopat

hy)

CK

350

U/L

Feat

ure

sofm

itoch

ondrial

myopat

hy

inm

usc

lebio

psy

from

moth

er

Pro

xim

allim

bw

eak

ness

,trunca

lw

eak

ness

Sever

edilat

ed

card

iom

yopat

hy

Bro

ther

Coro

nar

yar

tery

dis

eas

e,

ech

oca

rdio

gra

msh

ow

ed

mildly

dilat

ed

left

ventric

lean

dm

ild

mitra

lre

gurg

itat

ion,ECG

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.[2006]

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TABLE

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Pat

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Sex

Age

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s(y

ear

s)Clinic

alfe

ature

sRela

tives

with

R644C

Clinic

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LMNA mutations [Ludtke et al., 2005] although otherfeatures of FPLD were lacking in this patient.

Initially, the lack of segregation with phenotypeand the observation of nonpenetrance in carrierparents suggested that the c.1930C>T (R644C)missense change in LMNA may be a rare poly-morphism. The identification of the same change inan individual from a CEPH family [Speckmanet al., 2000] was consistent with this interpretation.However, there are several strands of evidencein support of its pathogenicity. Firstly, the R644Cchange has not been detected in 1,000 normalchromosomes tested by us (200 German and300 British controls; data not shown) nor in 250controls reported in the medical literature [Muntoniet al., 2006]. In contrast we have found nine patientswith features of laminopathy to harbor the R644Cmutation and eight further patients have beenreported in the literature [Genschel and Schmidt,2000; Csoka et al., 2004; Mercuri et al., 2005; Muntoniet al., 2006]. Secondly, the arginine (R) residue atposition 644 is highly conserved across severalspecies (human, mouse, rabbit, dog and Xenopustropicalis). It forms part of the RSYLLG hexapeptiderecognized by the prelamin A endoproteaseZMPSTE24 (or FACE1) which cleaves between theTyr657 (Y) and Leu658 (L) residues [Kilic et al., 1997].Removal of the 18 carboxy terminal amino acids byZMPSTE24 is an essential step in the production ofmature lamin A protein from its precursor prelaminA and failure of this process, either due to lack ofZMPSTE24 or to deletion of the cleavage site isknown to result in the severe laminopathies res-trictive dermopathy (RD) and Hutchinson Gilfordprogeria syndrome (HGPS), respectively [De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003; Navarroet al., 2005]. In addition, a different amino acidsubstitution at this codon, R644H, has been reportedin a child with a severe congenital muscular dys-trophy [Mercuri et al., 2005].

Nonpenetrance and variability of phenotype havebeen reported for other LMNA mutations. However,the R644C missense change reported here is the mostextreme example reported to date. Of seven patientswhere genetic testing of parents has been possible,four mothers and three fathers have been found toharbor the same change (parents of Patients 2, 3, 4, 5,8 and 9 above and patients published by Mercuriet al., 2005; Muntoni et al., 2006). Some of these havehad detailed clinical assessment including ECG andechocardiogram (see Table I). Any reported abnor-malities have been mild, for example a carrier fatherreported by Muntoni et al. [2006] was found to havemild subclinical evidence of muscle involvement onMRI and the carrier father of Patient 4 reported byMercuri et al. [2005] hadmildly elevatedCK (personalcommunication Joanna Poulton and Hugh Watkins)as did the mother and sibling of Patients 8 and9 reported here. In none of the known families do

typical features of laminopathy segregate clearlywith the R644C mutation.

The nonpenetrance and variable expressivity ofthe R644C mutation remain unexplained but severalhypotheses can be considered. Firstly, it is possiblethat R644C is a recessive mutation and that thepatients harbor a second unidentified LMNA muta-tion. All patients reported here, and to our knowl-edge all published patients, have been tested by fullsequencing of all LMNA exons and exon/intronboundaries. It is unlikely that a second mutationhas been missed in all 17 patients. Secondly, if thewild type LMNA gene were subject to imprinting, aphenotype in heterozygotes may be due to mono-allelic expression of the mutant allele. Interestingly,Zhou et al. [2006] recently found evidence of tissuespecific imprinting of the RYR1 gene on chromo-some 19 in the congenital myopathies centralcore disease and multiminicore disease. However,chromosome 1 (on which the LMNA gene is located)is not known to be imprinted and there is no parentof origin effect in the R644C families, three beingpaternally and four maternally inherited, meaningthat this is not a likely explanation. The third hypo-thesis, suggested by Muntoni et al. [2006], is perhapsthe most attractive. They found evidence of dualpathology in a family with the R644C mutation and inanother family with a different LMNA missensechange. Family 2 in their paper consisted of a motherand son with cardioskeletal myopathy. R644C wasfound in the son and his father (in whom onlysubclinical muscle involvement was found on MRI)and so did not segregate with disease. Furtheranalysis of the son’s skeletal and cardiac musclerevealed accumulationof desmin and subsequently anovel missense change in DES, the gene encodingdesmin, was identified. The father did not harborthe DES mutation but it was not possible to test thedeceased mother. The son had had a more severecardiomyopathy than the mother and the authorsproposed that the mother may have had desmino-pathy only whereas the son’s phenotype resultedfrom digenic inheritance of heterozygous mutationsin LMNA and DES. Family 1 in the same paper hadconfirmed X linked Emery Dreifuss muscular dys-trophy with an atypically severe phenotype in a maleharboringboth an STAmutation andanovel, denovoLMNA mutation (S326T). The authors note evidencefor interaction between lamin A/C and both emerinand desmin and suggest that digenic inheritanceof mutations in genes encoding functionally linkedproteins may occur. A further example of dualpathology is given by Mercuri et al. [2005]. In theirpaper, Patient 4 developed dilated cardiomyopathyas did his mother and brother, both of whom died.The R644C change was found in both the boys andthe unaffected father but not in the mother. Therewas muscle biopsy evidence of mitochondrialabnormalities in the brother and mother [Mercuri

1540 RANKIN ET AL.


et al., 2005 and Joanna Poulton, personal communi-cation; see Table I], suggesting an alternative dia-gnosis. However, the age of diagnosis ofcardiomyopathy was younger in the boys (8 and9 years) than in the mother (31 years) and so, again,the more severe phenotype in the boys may haveresulted from the combination of both a mitochon-drial disorder and the LMNAR644C mutation. Finally,Patient 6 in our series had evidence of a seconddiagnosis as he was found to have an abnormal resulton FSHD testing. Most patients with FSHD havea reduction in copy number of a subtelomericrepeat on chromosome 4q [Wijmenga et al., 1992]and EcoRI/BlnI double restriction digest reveals afragment of reduced size (<35 kb), the normal rangebeing >48 kb. Fragments of intermediate size (35–48 kb) are found in normal controls but are alsoassociated with mild FSHD, often with sparing offacial muscles. The finding of a 37 kb fragment inour patient raises the possibility that this is at leastpartially responsible for his phenotype. Intriguingly,Masny et al. [2004] provide evidence for a functionalinteraction between the 4q telomere and lamin A/Cby demonstrating that in fibroblasts lacking laminA/C the 4q telomere is not correctly localized to thenuclear envelope [Masny et al., 2004].

If digenic inheritance is the explanation for thevariable expressivity and nonpenetrance in allfamilies harboring the R644C change, then it isinteresting to consider what the second causativegene may be in other families. In those familieslacking muscle involvement, STA (encoding emerin)and DES (encoding desmin) are unlikely candidates.R644 formspart of the recognition site for the enzymeZMPSTE24 which catalyses an essential cleavagestep during processing of prelamin A to mature laminA. Most HGPS patients harbor a de novo splicingmutation which results in deletion of this ZMPSTE24recognition site and, in cultured cells, accumulationof unprocessed prelamin A [De Sandre-Giovannoliet al., 2003; Eriksson et al., 2003]. In addition, re-cessive mutations of the ZMPSTE24 gene resultin similar cellular accumulation of unprocessedprelamin A and a severe condition, restrictivedermopathy, considered to be a ‘secondary lamin-opathy’ [Navarro et al., 2005]. Recessive ZMPSTE24mutations have also been found in patients withfeatures of MAD [Agarwal et al., 2003]. TheZMPSTE24 gene is therefore a tempting candidateas reduction in activity of the enzyme alongwith alteration of its recognition site could resultin abnormal processing of prelamin A. We havesequenced this gene in threeR644Cpatients (Patients1, 2 and 8) but no mutations were found (data notshown). If this were the mechanism, then accumu-lation of unprocessed prelamin A would be expectedin cultured cells. Toth et al. [2005] studied fibroblastsfrom thepatientwith atypical progeria and theR644Cchange reported by Csoka et al. [2004]. Interestingly

they did not find accumulation of prelamin A butdid see abnormalities of nuclear shape typicallyseen in cultured cells from some patients withlaminopathies. Nevertheless, it would be interestingto examine cells from further patients carrying theR644C mutation.

In conclusion, this report brings the total numberof known c.1930C>T (R644C) heterozygotes to17 (nine described here and eight previouslypublished) and broadens the spectrum of reportedphenotypes for this mutation to include the esta-blished laminopathies Emery Dreifuss musculardystrophy, limb girdle muscular dystrophy, partiallipodystrophy, dilated cardiomyopathy and atypicalprogeria as well as unusual presentations such asptosis, isolated hepatic steatosis and motor neuro-pathy with pyramidal signs. The apparent non-penetrance of the c.1930C>T mutation in manyfirst degree relatives raises questions about thesignificance of the R644C missense change butthere is compelling evidence that it is pathogenic.In three families (one described here and twopreviously published) an additional pathologicalfeature (borderline FSHD fragment, DES mutationand mitochondrial myopathy) has been recognizedand may have contributed to the clinical presenta-tion. The mechanism of pathogenesis is unknownbut the observations in our families and in thosepreviously published provide evidence that the riskof clinical features of laminopathy in close relativesis likely to be low. However, until further data areavailable, clinical assessment of R644C mutationcarriers is warranted and should include a search forcardiomyopathy, diabetes and dyslipidemia.

ACKNOWLEDGMENTS

We are very grateful to all the patients forpermission to publish their details. WB thanks RickCutfield for leading him to the diagnosis in hispatient. The support of NTD by the Joint GraduateEducation Program of Deutscher AkademischerAustauschdienst (DAAD, VNM 04/A17) is acknowl-edged as well as the support of MSW by a grant of theBMBF (MD-NET, 01GM0302).

REFERENCES

Agarwal AK, Fryns JP, Auchus RJ, Garg A. 2003. Zinc metal-loproteinase, ZMPSTE24, is mutated in mandibuloacraldysplasia. Hum Mol Genet 12:1995–2001.

Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H,Fryns JP, Garg A. 2006. Focal segmental glomerulosclerosis inpatients with mandibuloacral dysplasia owing to ZMPSTE24deficiency. J Investig Med 54:208–213.

Benedetti S, Bertini E, Iannaccone S, Angelini C, Trisciani M,Toniolo D, Sferrazza B, Carrera P, Comi G, Ferrari M, QuattriniA, Previtali SC. 2005. Dominant LMNA mutations can causecombined muscular dystrophy and peripheral neuropathy.J Neurol Neurosurg Psychiatry 76:1019–1021.



Bonne G, Mercuri E, Muchir A, Urtizberea A, Becane HM, RecanD, Merlini L, Wehnert M, Boor R, Reuner U, Vorgerd M,Wicklein EM, Eymard B, Duboc D, Penisson-Besnier I, CuissetJM, Ferrer X, Desguerre I, Lacombe D, Bushby K, Pollitt C,Toniolo D, Fardeau M, Schwartz K, Muntoni F. 2000. Clinicaland molecular genetic spectrum of autosomal dominantEmery-Dreifuss muscular dystrophy due to mutations of thelamin A/C gene. Ann Neurol 48:170–180.

Brodsky GL, Muntoni F, Miocic S, Sinagra G, Sewry C, Mestroni L.2000. Lamin A/C gene mutation associated with dilatedcardiomyopathy with variable skeletal muscle involvement.Circulation 101:473–476.

Cao H, Hegele RA. 2000. Nuclear lamin A/C R482Q mutationin Canadian kindreds with Dunnigan-type familial partiallipodystrophy. Hum Mol Genet 9:109–112.

Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O,Cohen A, Courvalin JC, Laroche L, Capeau J, Vigouroux C,Christin-Maitre S. 2003. A new clinical condition linked to anovel mutation in lamins A and C with generalized lipoa-trophy, insulin-resistant diabetes, disseminated leukomela-nodermic papules, liver steatosis, and cardiomyopathy. J ClinEndocrinol Metab 88:1006–1013.

Csoka AB, Cao H, Sammak PJ, Constantinescu D, Schatten GP,Hegele RA. 2004. Novel lamin A/C gene (LMNA) mutations inatypical progeroid syndromes. J Med Genet 41:304–308.

De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J,Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M,Levy N. 2003. Lamin A truncation in Hutchinson-Gilfordprogeria. Science 300:2055.

Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L,Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E,Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. 2003.Recurrent de novo point mutations in lamin A causeHutchinson-Gilford progeria syndrome. Nature 423:293–2298.

Genschel J, Schmidt HH. 2000. Mutations in the LMNA geneencoding lamin A/C. Hum Mutat 16:451–459.

Goizet C, Yaou RB, Demay L, Richard P, Bouillot S, Rouanet M,Hermosilla E, Le Masson G, Lagueny A, Bonne G, Ferrer X.2004. A new mutation of the lamin A/C gene leading toautosomal dominant axonal neuropathy,muscular dystrophy,cardiac disease, and leuconychia. J Med Genet 41:e29.

Javor ED,Moran SA,Young JR, Cochran EK, Depaoli AM, Oral EA,Turman MA, Blackett PR, Savage DB, O’Rahilly S, Balow JE,Gorden P. 2004. Proteinuric nephropathy in acquired andcongenital generalized lipodystrophy: Baseline character-istics and course during recombinant leptin therapy. J ClinEndocrinol Metab 89:3199–3207.

Kilic F, Dalton MB, Burrell SK, Mayer JP, Patterson SD, SinenskyM. 1997. In vitro assay and characterization of the farnesyla-tion-dependent prelamin A endoprotease. J Biol Chem272:5298–5304.

Ludtke A, Genschel J, Brabant G, Bauditz J, Taupitz M, Koch M,Wermke W, Worman HJ, Schmidt HH. 2005. Hepatic steatosisin Dunnigan-type familial partial lipodystrophy. Am J Gastro-enterol 100:2218–2224.

Masny PS, Bengtsson U, Chung SA, Martin JH, van Engelen B, vander Maarel SM, Winokur ST. 2004. Localization of 4q35.2 to thenuclear periphery: Is FSHD a nuclear envelope disease? HumMol Genet 13:1857–1871.

Mercuri E, Poppe M, Quinlivan R, Messina S, Kinali M, Demay L,Bourke J, Richard P, Sewry C, Pike M, Bonne G, Muntoni F,Bushby K. 2004. Extreme variability of phenotype in patientswith an identical missense mutation in the lamin A/C gene:from congenital onset with severe phenotype to milder classicEmery-Dreifuss variant. Arch Neurol 61:690–694.

Mercuri E, Brown SC, Nihoyannopoulos P, Poulton J, Kinali M,Richard P, Piercy RJ, Messina S, Sewry C, Burke MM, McKennaW, Bonne G, Muntoni F. 2005. Extreme variability of skeletaland cardiac muscle involvement in patients with mutations inexon 11 of the lamin A/C gene. Muscle Nerve 31:602–609.

Muntoni F, Bonne G, Goldfarb LG, Mercuri E, Piercy RJ, Burke M,Yaou RB, Richard P, Recan D, Shatunov A, Sewry CA, BrownSC. 2006. Disease severity in dominant Emery Dreifuss isincreased by mutations in both emerin and desmin proteins.Brain 129:1260–1268.

Navarro CL, Cadinanos J, De Sandre-Giovannoli A, Bernard R,Courrier S, Boccaccio I, Boyer A, Kleijer WJ, Wagner A,Giuliano F, Beemer FA, Freije JM, Cau P, Hennekam RC,Lopez-Otin C, Badens C, Levy N. 2005. Loss of ZMPSTE24(FACE-1) causes autosomal recessive restrictive dermopathyand accumulation of lamin A precursors. Hum Mol Genet 14:1503–1513.

Owen KR, Donohoe M, Ellard S, Clarke TJ, Nicholls AJ, HattersleyAT, Bingham C. 2004. Mesangiocapillary glomerulonephritistype 2 associated with familial partial lipodystrophy (Dunni-gan–Kobberling syndrome). Nephron Clin Pract 96:c35–c38.

Rankin J, Ellard S. 2006. The laminopathies: A clinical review. ClinGenet 70:261–274.

Shackleton S, LloydDJ, Jackson SN, Evans R,NiermeijerMF, SinghBM, Schmidt H, Brabant G, Kumar S, Durrington PN, GregoryS, O’Rahilly S, Trembath RC. 2000. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet 24:153–156.

Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, TaylorSI, Lovett M, Bowcock AM. 2000. Mutational and haplotypeanalyses of families with familial partial lipodystrophy(Dunnigan variety) reveal recurrent missense mutations inthe globular C-terminal domain of lamin A/C. Am J HumGenet 66:1192–1198.

TazirM,Azzedine H,Assami S, SindouP, Nouioua S, Zemmouri R,Hamadouche T, Chaouch M, Feingold J, Vallat JM, Leguern E,Grid D. 2004. Phenotypic variability in autosomal recessiveaxonal Charcot–Marie–Tooth disease due to the R298Cmutation in lamin A/C. Brain 127:154–163.

Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL,Miner JH, Young SG, Fong LG. 2005. Blocking proteinfarnesyltransferase improves nuclear shape in fibroblastsfrom humans with progeroid syndromes. Proc Natl Acad SciUSA 102:12873–12878.

Van Esch H, Agarwal AK, Debeer P, Fryns JP, Garg A. 2006. Ahomozygous mutation in the lamin a/c gene associated with anovel syndrome of arthropathy, tendinous calcinosis, andprogeroid features. J Clin Endocrinol Metab 91:517–521.

Vantyghem MC, Pigny P, Maurage CA, Rouaix-Emery N, StojkovicT, Cuisset JM, Millaire A, Lascols O, Vermersch P, Wemeau JL,Capeau J, Vigouroux C. 2004. Patients with familial partiallipodystrophy of the Dunnigan type due to a LMNA R482Wmutation show muscular and cardiac abnormalities. J ClinEndocrinol Metab 89:5337–5346.

VytopilM, Ricci E, Dello RussoA, Hanisch F, Neudecker S, Zierz S,Ricotti R, Demay L, Richard P, Wehnert M, Bonne G, Merlini L,Toniolo D. 2002. Frequent low penetrance mutations in thelamin A/C gene, causing Emery Dreifuss muscular dystrophy.Neuromuscul Disord 12:958–963.

Walter MC, Witt TN, Weigel BS, Reilich P, Richard P, Pongratz D,Bonne G, Wehnert MS, Lochmuller H. 2005. Deletion of theLMNA initiator codon leading to a neurogenic variant ofautosomal dominant Emery-Dreifuss muscular dystrophy.Neuromuscul Disord 15:40–44.

Wijmenga C, Hewitt JE, Sandkuijl LA, Clark LN, Wright TJ,Dauwerse HG, Gruter AM, Hofker MH, Moerer P, WilliamsonR, van Ommen GJ, Padberg GW, Frants RR. 1992. Chromo-some 4q DNA rearrangements associated with facioscapulo-humeral muscular dystrophy. Nat Genet 2:26–30.

Young J, Morbois-Trabut L, Couzinet B, Lascols O, Dion E,Bereziat V, Feve B, Richard I, Capeau J, Chanson P, VigourouxC. 2005. Type A insulin resistance syndrome revealing a novellamin A mutation. Diabetes 54:1873–1878.

Zhou H, Brockington M, Jungbluth H, Monk D, Stanier P, SewryCA, Moore GE, Muntoni F. 2006. Epigenetic allele silencingunveils recessive RYR1 mutations in core myopathies. AmJ Hum Genet 79:859–868.

1542 RANKIN ET AL.


extreme phenotypic diversity and nonpenetrance in families with the lmna gene mutation r644c

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