Am. J. Hum. Genet. 62:i–ii, 1998

i

This Month in the JournalThis month we present two review articles related to thegenetics of resistance to pathogens. Brownstein (p. 211)discusses variability, in humans and among different in-bred mouse strains, in susceptibility to viruses. He con-siders both the celebrated recent example of a chemokinereceptor polymorphism that protects from HIV infectionand also some more subtle, but possibly more represen-tative, examples of polymorphisms that influence theprogression of viral disease. Poland (p. 215) focuses onresistance to measles. He argues that antiviral antibody-titer following vaccination represents a quantitative phe-notype that reflects the host’s resistance to active path-ogens. Genes that modulate responses to measles-virusvaccination include the major histocompatibility lociand the TAP genes, which function in antigen processing.

Multiple Endocrine Neoplasia Type I, by Bassett et al.(p. 232)

Menin is the product of the recently cloned MEN1 gene,which underlies type I multiple endocrine neoplasia, amultiple-tumor disorder sometimes associated with pep-tic ulcers. The dominant inheritance and variable clinicalcourse of MEN1 may indicate that menin serves as atumor suppressor, but its biochemical function has notbeen demonstrated, and its sequence offers few clues.Bassett et al. have used SSCP and DNA sequencing toidentify constitutional MEN1 mutations in 61 of 63 un-related MEN1 probands, 57 of whom had family his-tories of the disease. In all, they identified 47 distinctmutations, all point mutations or short deletions or in-sertions. The mutations are found throughout the exonsand the exon junctions in MEN1, and the authors couldfind no correlation between the type or location of themutation and the disease phenotype. The number of dis-ease alleles and the frequent occurrence of de novo mu-tations, often at hot spots with short repeat sequences,suggest that haplotype analysis is of limited use fordiagnosis.

Mutation Analysis of Leiomyomatosis, by Ueki et al.(p. 253)

The X-linked form of Alport syndrome (AS), a kidneydisease that also presents with eye defects and deafness,results from mutations in the COL4A5 gene, encodingone of the basement-membrane collagen chains. Whendeletions in COL4A5 extend into the neighboring col-lagen gene COL4A6, AS may be accompanied by diffuse

� 1998 by The American Society of Human Genetics. All rights reserved.0002-9297/98/6202-0001$02.00

leiomyomatosis (DL), a smooth-muscle tumor that char-acteristically affects the esophagus. Curiously, larger ge-netic lesions that completely eliminate both collagengenes present only with AS. A critical region ofCOL4A6, including some of its third intron, needs tobe spared for DL to occur. It has been proposed thatthis intron contains structural or regulatory elements ofa third, as yet unidentified, gene that represses DL; al-ternatively, a truncated form of COL4A6 might affectsmooth-muscle-cell growth directly. Ueki et al. now re-port the sequence flanking the COL4A6 breakpoint ina man with AS and DL, a first step toward resolvingthis question. They find multiple consensus sequencesfor topoisomerases surrounding the breakpoints. Thismay suggest a mechanism for somatic deletion in theCOL4A5/ COL4A6 region, but the reason for pheno-type differences between short and long COL4A6 de-letions remains mysterious.

Pathogenic Mutation in Human Complex I, by vanden Heuvel et al. (p. 262)

Respiratory electron-transport chains create the protongradients needed for oxidative phosphorylation, and de-fects in the electron carriers in this process can lead tomitochondrial dysfunction and fatal encephalomyopa-thies. Electron-transport complexes are large multicom-ponent assemblies. Complex I contains the products ofat least 42 genes, most of which are nuclear; defects incomplex I function are readily identified at the biochem-ical level, but genetic analysis has been lacking. van denHeuvel et al. have undertaken to find the causal muta-tions in a set of 20 complex I–deficient individuals. Theyused homology to a known bovine sequence to identifya human cDNA for the AQDQ subunit of complex I,which they report here. One of the 20 individuals ishomozygous for a 5-bp insertion that shifts the readingframe and extends the C-terminus of the AQDQ protein.

Stop Codons of NF1 as Splice Effectors, by Hoffmeyeret al. (p. 269)

Nuclear-scanning mechanisms have been invoked to ex-plain the sensitivity of intranuclear pre-mRNA splicingand degradation to breaks in the reading frame of nas-cent mRNA. Although appealing on teleologicalgrounds, and apparently supported in the case of fibrillinmRNA splicing, nuclear scanning remains controversialbecause there is no obvious mechanism for sensing pre-mature-termination codons (PTCs) in the nucleus. Sev-eral groups, including, now, Hoffmeyer et al., have

Am. J. Hum. Genet. 62:i–ii, 1998

ii

sought alternative explanations for the skipping of exonsthat contain PTCs. Working with RNA from cells frompeople with type I neurofibromatosis, Hoffmeyer andcolleagues show that the processing of neurofibrominmRNA does not respond simply to the presence of PTCsin an internal exon. In sets of alleles with mutations inexon 7 or exon 37 of the 61-exon NF1 gene, they findthat neighboring PTCs may have different effects onmRNA splicing or stability. They further argue that pre-dicted changes in RNA secondary structure, which mayintroduce, remove, or destroy sequences that participatein splicing, can account for the observed effects of PTCsin this mRNA species.

Methylation Analysis in the DMPK Gene, bySteinbach et al. (p. 278)

Methylation of DNA in CpG islands, noncoding regionsenriched for CpG dinucleotides, is associated withchanges in chromatin structure and transcriptional ac-tivity. Here, Steinbach and coworkers describe a corre-lation between a trinucleotide-repeat expansion in dis-ease alleles of the myotonic dystrophy (DM) gene,DMPK, and the complete methylation of CpG siteswithin 1.5 kb of the trinucleotide repeat. This hyper-methylation is found in cases of congenital DM but notin later-onset cases or in unaffected individuals. Bindingof transcription factor Sp1 to a site near the repeat isalso inhibited, suggesting that with hypermethylationcomes a compact chromatin structure and reducedDMPK expression. These observations are consistentwith other reports of effects of repeat expansion on localmethylation, but they do not readily account for thedominant effects observed for the DM disease allele.

CYP1B1 Mutations in GLC3A, by Bejjani et al. (p.325)

Here, Bejjani et al. report novel missense mutations inthe cytochrome P450 gene, CYP1B1, that lead to pri-mary congenital glaucoma. The association of CYP1B1with this condition was recently reported in some Turk-ish glaucoma families. In the Saudi group studied byBejjani et al., the genetic basis of the disease appears tobe simpler. All affected individuals in 25 families wereeither compound heterozygotes or homozygotes for oneof three missense mutations. These findings may be use-ful for structure/function analysis, as well as for geneticcounseling in the Saudi population. The connection be-tween these mutations and PCG, however, remains un-clear; Bejjani and colleagues speculate that CYP1B1 mayhelp degrade endogenous growth or differentiation fac-tors during ocular development.

Susceptibility to Relapsing-Progressive MS, byHockertz et al. (p. 373)

Statistical analysis of human patients and experimentalwork in animals indicate a role for T cell–receptor (TCR)genes and class II MHC genes in multiple sclerosis (MS).These candidate loci are plausible, because MS is a de-myelination disorder that probably develops from au-toimmune reactions. Nevertheless, detailed analysis hasproved difficult, in part because of complex allele-spe-cific interactions between these loci. Hockertz and co-workers argue here that two factors—the failure to dis-tinguish among clinical forms of the disease and theimproper choice of control populations—have led re-searchers to contradictory conclusions. Here, they em-ploy family-based controls and stratify their group forpatterns of disease progression. They find that two dis-tinct genotypes, consisting of different haplotypes at theTCR locus and a polymorphism at the HLA-DR locus,are significantly associated with the relapsing-progres-sive—but not with the relapsing-remitting—form of thedisease.

mtDNA in Aboriginal Australians, by van HolstPellekaan et al. (p. 435)

mtDNA sequence divergence provides the basis for muchof the genetic reconstruction of human migrations, butthis technique has not been applied extensively to Aus-tralian aboriginal peoples. van Holst Pellekaan et al.have acquired DNA samples from two culturally andlinguistically distinct groups, one from the north-central“desert” region and one from the “riverine” region ofsoutheastern Australia. They also developed a novel met-ric for mtDNA sequence divergence, BEPPI, the between-population proportion index. This statistic describes therelation between the number of sequence differences ina sample and the proportion of all sequence pairingsthat compare DNAs from different groups. They finddistinct distributions of mtDNA sequence types betweenthe desert and riverine peoples, consistent with their as-sumed isolation. Comparisons with outside groups showthat the aboriginal populations are most closely relatedto each other and that they are genetically nearer to NewGuinea highlanders than to other Pacific or African peo-ples. This reconstruction is consistent with anthropo-logical and genetic evidence suggesting a common foun-der population for the present-day Australian aboriginesand New Guinea highlanders.

JOHN ASHKENAS

Editorial Fellow