Exposing the human nude phenotype

Abstract

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...

An autosomal dominant form of hereditary hypotrichosis simplex maps to 18p11.32–p11.23 in an Italian family

“…1,6,7 Despite published accounts of literally hundreds of Mendelian hair-growth disorders, the defective genes have been identified only in a few so far. These include anhidrotic ectodermal dysplasia (MIM 305100; 3 MIM 224900 8 ), monilethrix (MIM 252200 9,10 ), autosomal recessive congenital universal atrichia (MIM 203655 2,7,11,12 ), and congenital atrichia with severe functional T-cell immunodeficiency and nail dystrophy (MIM 601705 13 ).…”

Successes and risks of gene therapy in primary immunodeficiencies

“…[1][2][3] For example, 12 different genotypes have been identified for severe combined immunodeficiency (SCID; Table I). [4][5][6][7][8] However, advances in finding the causes and explaining the pathophysiology of PIs have not yet been paralleled with similar progress in the development of safe and curative treatments. Patients with immunodeficiency have experienced considerable benefit from medical advances in supportive therapy, including the prophylaxis and treatment of infections, the management of chronic respiratory and gastrointestinal diseases, and the treatment of secondary neoplasias.…”

Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus

“…nactivating mutations in the forkhead box N1 (Foxn1) gene cause the athymic "nude" phenotype in humans, rats, and mice (1,2). The 10 Foxn1 exons encode a 648-aa transcription factor of the forkhead box family.…”