There are several forms of hereditary human hair loss, known collectively as alopecias, the molecular bases of which are entirely unknown. A kindred with a rare, recessively inherited type of alopecia universalis was used to search for a locus by homozygosity mapping, and linkage was established in a 6-centimorgan interval on chromosome 8p12 (the logarithm of the odds favoring linkage score was 6.19). The human homolog of a murine gene, hairless, was localized in this interval by radiation hybrid mapping, and a missense mutation was found in affected individuals. Human hairless encodes a putative single zinc finger transcription factor protein with restricted expression in the brain and skin.
The recent discovery of the human coun-terpart of the hairlessmousephenotype1has helped our understandingof the molecular genetics of hair growth.But there are no reports of a defect in thehuman homologue of the best known of the'bald' mouse phenotypes, the nudemouse2.This may be because affected individualsare so gravely ill from the accompanyingimmunodeficiency that their baldness goesunnoticed. We have carried out a geneticanalysis that reveals a human homologue ofthe nudemouse.The nudemouse is characterized by acongenital absence of hair and a severeimmunodeficiency2, resulting from muta-tions in the whn(winged-helix-nude;Hfh11nu) gene, which encodes a member ofthe forkhead/winged-helix transcriptionfactor family with restricted expression inthymus and skin3. The simultaneous occur-rence of severe functional T-cell immunodeficiency, congenital alopecia and nail dys-trophy (MIM database no. 601705) in twoaffected sisters led to the recognition thatthe clinical phenotype was reminiscent ofthe nudemouse4. We therefore investigatedwhether this syndrome represents thehuman counterpart of the nudemousephenotype.We obtained DNA samples from mem-bers of the sisters' family in a small villagein southern Italy. The affected sisters wereborn with a complete absence of scalp hair (Fig. 1a), eyebrows and eyelashes and haddystrophic nails, and no thymic shadow wasevident upon X-ray examination. The firstaffected child revealed a striking impair-ment of T-cell function shortly after birth,and died at the age of 12 months. Her sisterhad similar immunological abnormalities,but bonemarrow transplantation at fivemonths of age led to full immunologicalreconstitution, although the alopecia andnail dystrophy are still present4.We performed linkage analysis usingmicrosatellite markers near the humanWHNlocus on chromosome 17, and founda lod score of 1.32, suggestive of linkage. Wethen sequenced the human WHNgene5andfound a homozygous C-to-T transition atnucleotide position 792 of the WHNcDNA(GenBank accession no. Y11739) (Fig. 1b).This leads to a nonsense mutation atresidue 255 (R255X) in exon 5, and predictsthe complete absence of functional proteinas a result of nonsense-mediated decay ofmessenger RNA.Because the proband's bonemarrowtransplant was from her brother, we exam-ined her leukocyte DNA both before andafter the graft for the presence of chi-maerism. Genotyping the proband beforethe transplant showed that her leukocyteDNA was homozygous only for the mutantallele (Fig. 1c). Four years after the transplant, we detected the haplotype specific forthe wild-type paternal WHNallele receivedfrom the brother, as well as the mutantallele, indicative of chimaerism. Genderdetermination revealed that the proband'sleukocyte DNA was genotypically XXbefore the transplant, and the brother'sDNA was XY. Afterwards, the proband'sleukocyte DNA was found to be XY (Fig.1c), providing evidence of longtermengraftment and expansion of the bone-marrow graft.The WHNgene encodes a transcriptionfactor, which is developmentally regulatedand directs cel...
Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of =2 cM, in the largest multigenerational BP pedigree series reported to date. A two-point heterogeneity (alpha=0.5) LOD score of 3.35 (P<.000156) was found at the D21S1260 locus, 5 cM proximal to PFKL. Polylocus analysis with a cluster of three neighboring markers was consistent with these results (PL-HetLOD = 3.25). In the design of this study, 373 individuals from 40 families (from a total set of 1,508 individuals in 57 families) were chosen, as a cost-effective approach to genotyping this large sample set. Linkage analyses were performed with an "affecteds-only" method. As such, our results are based solely on genetic information from affected individuals, without assumptions about the disease-locus genotypes of the unaffecteds. Furthermore, for ease of comparison, this study was performed with the same approach as a 10-cM genome scan for BP loci, the results of which will be reported elsewhere.
Cell adhesion and communication are interdependent aspects of cell behavior that are critical for morphogenesis and tissue architecture. In the skin, epidermal adhesion is mediated in part by specialized cell-cell junctions known as desmosomes, which are characterized by the presence of desmosomal cadherins, known as desmogleins and desmocollins. We identified a cadherin family member, desmoglein 4, which is expressed in the suprabasal epidermis and hair follicle. The essential role of desmoglein 4 in skin was established by identifying mutations in families with inherited hypotrichosis, as well as in the lanceolate hair mouse. We also show that DSG4 is an autoantigen in pemphigus vulgaris. Characterization of the phenotype of naturally occurring mutant mice revealed disruption of desmosomal adhesion and perturbations in keratinocyte behavior. We provide evidence that desmoglein 4 is a key mediator of keratinocyte cell adhesion in the hair follicle, where it coordinates the transition from proliferation to differentiation.
The papers on HLA and mate choice, by Hedrick and Black (1997), who studied South Amerindian tribes, and by Ober et al. (1997), who studied the relatively closed and partially inbred Hutterite populations, as well as the invited editorial by Beauchamp and Yamazaki (1997), point out the conflicting evidence for this potential relationship and some of the possible reasons for it. I would like to suggest an alternative approach. My colleagues and I have shown that there is a relationship between recurrent spontaneous abortion and genes linked to HLA-DR and between unexplained infertility and genes linked to HLA-DQ (Gill 1992; Jin et al. 1995). It is important to note that the data showed that genes linked to the genes encoding HLA antigens-and not the HLA genes themselves-are involved in these associations between HLA and reproductive defects. The same conclusion has been proposed for the association between HLA and susceptibility to rheumatoid arthritis (Dizier et al. 1993), between HLA-DR and HLA-DQ and insulin-dependent diabetes mellitus (Clerget-Darpoux et al. 1991; Dizier et al. 1994), and between HLA and multiple sclerosis (Francis et al. 1991). I propose that the potential association between HLA and mate selection may reside in the HLA-B-DR-DQ region and that this association should be explored in detail. Inclusion of the HLA-A locus in the analysis can obscure this potential effect considerably (Ho et al. 1994). Hedrick and Black (1997) typed only for HLA-A and HLA-B, and Ober et al. (1997) did not give the details of the genetic structure of the haplotypes in the various mating combinations. The latter group, however, has published on the relationship between HLA-DR and fertilization or implantation in the same Hutterite populations (Ober et al. 1992; Ober 1995); thus, it seems reasonable that, if mate selection has an association with genes in the HLA complex, these genes may reside in the HLA-B-DR-DQ region. If a relationship between the major histocompatibility complex (MHC) and mate selection is borne out in humans , it may reflect an evolutionary reproductive drive to avoid homozygosity for MHC-linked recessive reproductive genetic defects (Gill 1997a, 1997b). It is interesting to speculate that this type of evolutionary drive may also be the basis for the near-universal human taboo against incest.
Congenital atrichia with papular lesions is a rare, recessively inherited form of hair loss characterized by a complete absence of all body hair shortly after birth. Mutations in the human ortholog of the mouse hairless (hr) gene have been implicated in the pathogenesis of this disorder. In this study, we screened, by direct sequence analysis, the hairless gene in a family of Polish descent and identified a novel missense mutation (C622G). The mutation alters the third of four invariant cysteins in the zinc-finger domain, which has high homology to the C-X-X-C-(X)17-C-X-X-C structure of the zinc-fingers of the GATA family of transcription factors. The human hairless gene encodes a putative transcription factor with restricted expression in the brain and skin, which is involved in the regulation of apoptosis during catagen remodeling in the hair cycle.
Variegate porphyria (VP; OMIM 176200) is characterized by a partial defect in the activity of protoporphyrinogen oxidase (PPO), the seventh enzyme of the porphyrin-heme biosynthetic pathway. The disease is usually inherited as an autosomal dominant trait displaying incomplete penetrance. In an effort to characterize the spectrum of molecular defects in VP, we identified 3 distinct mutations in 6 VP families from Chile by PCR, heteroduplex analysis, automated sequencing, restriction enzyme digestion and haplotyping analysis. The mutations consisted of 2 deletions and 1 missense mutation, designated 1239delTACAC, 1330delT and R168H. The occurrence of the missense mutation R168H had been reported previously in American, German and Dutch VP families, suggesting that this may represent a frequent recurrent mutation. Interestingly, the mutation 1239delTACAC was found in patients from 4 unrelated families living in different parts of Chile, suggesting that it might represent a common mutation in Chile. Haplotype analysis using 15 microsatellite markers which closely flank the PPO gene on chromosome 1q22, spanning approximately 21 cM, revealed the presence of R168H on different haplotypes in 6 VP patients from 3 unrelated families. In contrast, we found the occurrence of 1239delTACAC on the same chromosome 1 haplotype in 11 mutation carriers from 4 unrelated families with VP. These findings are consistent with R168H representing a hotspot mutation and 1239delTACAC existing as a founder mutation in the PPO gene. Our data comprise the first genetic studies of the porphyrias in South America and will streamline the elucidation of the genetic defects in VP patients from Chile by allowing an initial screening for the founder mutation 1239delTACAC.
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