comment on elejalde syndrome and relationship with griscelli syndrome
TRANSCRIPT
American Journal of Medical Genetics 116A:408–409 (2003)
Correspondence
Comment on Elejalde Syndrome and RelationshipWith Griscelli Syndrome
To the Editor:
In their interesting report about Elejalde syndrome(ES), Ivanovich et al. [2001] discussed the complex rela-tionship of this disease with Griscelli syndrome (GS).Unfortunately, their report was submitted shortlybefore the publication of new data about moleculargenetics of GS that have by now defined the relationshipof ES and GS [Menasche et al., 2000]. GS is a rareautosomal recessive disease with hypopigmentationand hemophagocytic lymphohistiocytosis underlied bydeficient lymphocyte cytotoxicity and variable neuro-logical defects [Klein et al., 1994]. ES, or melanolysoso-mal neurocutaneous syndrome, is a rare autosomalrecessive disease, which as its name indicates, associ-ates hypopigmentation and profound central nervoussystem dysfunction [Elejalde et al., 1979; Duran-McKinster et al., 1999]. ES and GS bear a strikingresemblance in that, in both diseases, hypopigmenta-tion manifests as silvery hair, and is underlied bydefective melanosome transport in melanocytes. Themyosin Va gene (MYOVA) was the first gene involved inGS [Pastural et al., 1997]. Noticeably, these MYOVAmutations were found in patients, who, apart fromsilvery hair, presented early-onset severe psychomotorretardation, but no immune deficiency [Menasche et al.,2000]. The murine dilute phenotype, consisting of coatcolor dilution and severe neurological defects is alsocaused by mutations of MYOVA [Mercer et al., 1991].Confirming genetic data, it was shown that myosin Varegulates organelle transport in melanocytes and inneuronal cells [Reck-Peterson et al., 2000]. However, inother GS patients, it was demonstrated that the Rab27agene (RAB27A) is mutated. Noticeably, apart frompartial albinism, patients with RAB27A mutationspresented hemophagocytic lymphohistiocytosis, but no
primary neurological disease [Menasche et al., 2000].The murine ashen phenotype, consisting of coat colordilution and deficient cytotoxic lymphocyte activity, isalso caused by a mutation in RAB27A [Wilson et al.,2000]. Confirming genetic data we studied the melano-cytes of a GS patient with a nonsense mutation inRAB27A and established the key-role of Rab27a inmelanosome transport [Menasche et al., 2000], whileothers showed that Rab27a is required for cytotoxicgranule exocytosis [Menasche et al., 2000;Haddad et al.,2001; Stinchcombe et al., 2001]. These data shed a newlight on the relationship of ES and GS. Mutations ofMYOVA result in the cutaneousandneurological formofGriscelli syndrome or Griscelli syndrome type 1 thatlikely corresponds to Elejalde syndrome, and dilute isthe corresponding mouse model. On the other hand,mutations in RAB27A account for the cutaneous andimmunological form of Griscelli syndrome or Griscellisyndrome type 2, and ashen is the corresponding mousemodel. The possible occurrence of neurological symp-toms caused by hemophagocytic syndrome in the secondsubset of patients probably explains why this clarifica-tion could not be made before molecular data becameavailable.
REFERENCES
Duran-McKinster C, Rodriguez-Jurado R, Ridaura C, de la Luz Orozco-Covarrubias M, Tamayo L, Ruiz-Maldonando R. 1999. Elejalde syn-drome—a melanolysosomal neurocutaneous syndrome: clinical andmorphological findings in 7 patients. Arch Dermatol 135:182–186.
Elejalde R, Holguin J, Valencia A, Gilbert EF, Molina D, Marin G, ArangoLA. 1979. Mutations affecting pigmentation in man: neuroectodermalmelanolysosomal disease. Am J Med Genet 3:65–80.
Haddad E, Xufeng W, Hammer J, Henkart P. 2001. Defective granuleexocytosis in Rab27a-deficient lymphocytes from ashenmice. J Cell Biol152:835–841.
Ivanovich J, Mallory S, Storer T, Ciske D, Hing A. 2001. 12-year-old malewith Elejalde syndrome (neuroectodermal melanolysosomal disease).Am J Med Genet 98:313–316.
Klein C, Philippe N, Le Deist F, Fraitag S, Prost C, Durandy A, Fischer A,Griscelli C. 1994. Partial albinism with immunodeficiency (Griscellisyndrome). J Pediatr 125:886–895.
Menasche G, Pastural E, Feldmann J, Certain S, Ersoy F, Dupuis S,Wulffraat N, Bianchi D, Fischer A, Le Deist F, de Saint Basile G. 2000.Mutations in RAB27A cause Griscelli syndrome associated withhemophagocytic syndrome. Nat Genet 25:173–176.
Mercer G, Seperack P, Strobel M, Copeland N, Jenkins N. 1992. Novelmyosin heavy chain encoded by murine dilute coat color locus. Nature349:709–713.
*Correspondence to: Philippe Bahadoran, Unite INSERM 385,Faculte de Medecine, 06107 Nice cedex 2, France.E-mail: [email protected]
Received 3 September 2001; Accepted 6 February 2002
DOI 10.1002/ajmg.a.10065
� 2002 Wiley-Liss, Inc.
Pastural E, Barrat FJ, Dufourcq-Lagelouse R, Certain S, Sanal O, JabadoN, Seger R, Griscelli C, Fischer A, de Saint Basile G. 1997. Griscellidisease maps to chromosome 15q21 and is associated with mutations inthe myosin-Va gene. Nat Genet 16:289–292.
Reck-Peterson S, Provance W, Mooseker M, Mercer J. 2000. Class Vmyosins. Biochim Biophys Acta 1496:36–51.
Stinchcombe J, Barral D, Mules E, Booth S, Hume AN, Machesky LM,Seabra MC, Griffiths GM. 2001. Rab27a is required for regulatedsecretion in cytotoxic T-lymphocytes. J Cell Biol 152:825–833.
Wilson S, Yip R, Swing D, O’Sullivan TN, Zhang Y, Novak EK, Swank RT,Russell LB, Copeland NG, Jenkins NA. 2000. A mutation in Rab27acauses the vesicle transport observed in ashen mice. Proc Natl Acad SciUSA 97:7933–7938.
Philippe Bahadoran*Jean-Paul OrtonneRobert BallottiUnite INSERM 385,Faculte de Medecine, Nice, France
Genevieve de Saint-BasileUnite INSERM 429Hopital Necker-Enfants MaladesParis, France
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