There are several forms of hereditary human hair loss, known collectively as alopecias, which vary in age of onset, severity, and associated ectodermal abnormalities. Genetic conditions affecting hair structure or the hair growth cycle may be isolated or they may occur as part of complex syndromes with associated abnormalities of other ectodermal appendages.
For the present study, seven highly consanguineous families (A-G) with hereditary alopecias have been ascertained from different regions of Pakistan. The pattern of inheritance in all families has been observed as autosomal recessive.
In family A with alopecia and mental retardation syndrome, affected individuals were born with total alopecia and mild to moderate mental retardation. Screening of the human genome led to the identification of a novel locus, APMR2, on chromosome 3q26.2-q26.31. Significant evidence of linkage to this chromosomal region was found with maximum multipoint LOD score of 4.57 with several markers. Haplotype analysis located the APMR2 locus in 9.6 cM (5.6 Mb) region flanked by markers D3Sl564 and D3S2427. One of the candidate genes, TNFSF10, located in the linkage interval was screened in two affected and one normal individual; however, no disease causing mutation was detected.
In family B with alopecia and mental retardation syndrome, affected individuals showed total alopecia with severe mental retardation. Genome scan resulted in localization of a novel locus for alopecia and mental retardation syndrome, APMR3, to chromosome 18q11.2-q12.2. A maximum multipoint LOD score of 4.03 was obtained with several markers. The APMR3 linkage interval spans to a 10.9 cM (12.17 Mb) region flanked by markers D18S866 and D18S811. Nine candidate genes including, DSG1, DSG3, DSG4, DSC1, DSC3, ZNF397, ZNF271, ZNF24, and ZNF396 within linkage interval of APMR3 were screened in two affected and one normal individual. Sequence analysis, however failed to detect any functional variant.
In two consanguineous families (C and D), with localized autosomal recessive hypotrichosis segregating as a single abnormality without associated defects, a novel locus (LAH3) was mapped to chromosome 13q14.11-q21.32. Significant evidence of linkage to this chromosomal region was found with a maximum two-point LOD score of 4.79 and maximum multipoint LOD score of 5.9 with several markers. Due to consanguineous nature in these two families, the gene for LAH3 is probably contained within a 17.35 cM (24.41 Mb) region flanked by markers D13S325 and D13S1231. This linkage interval contains several genes including MED4 gene, which was screened for pathogenic mutation, but failed to identify any functional sequence variant.
In family E, affected individuals exhibited typical features of congenital alopecia. Genome scan was carried out using 396 highly polymorphic microsatellite markers. The linkage data obtained from genome scan and further saturation of the four chromosomal regions failed to define a region harboring a causative gene for congenital alopecia.
Two other families (F and G), demonstrating congenital atrichia and papular lesions, were found to be linked to HR gene on chromosome 8p21.3. Sequence analysis of exon 2 of the HR gene in affected individuals of family F revealed an insertion of 11 bp repeat sequence at nucleotide position 202 [202(InsCTTCCCCCAGG)]. In family G, the entire coding region, as well as the intron-exon boundaries of HR' gene were. sequenced in two affected and one normal individual, but failed to identify functional sequence variant suggesting that the mutation is probably present in the regulatory sequences of the gene.
The work presented in the thesis has been published in the following articles.
1. Wali A, Ansar M, Khan MN, Ahmad W. Atrichia with papular lesions resulting from a novel insertion mutation in the human hairless gene. Clinical and Experimental Dermatology 31(5): 695-698,2006.
2. Wali A, John P, Gul A, Lee K, Chishti MS, A1i G, Hassan MJ, Leal SM, Ahmad W. A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31. Clinical Genetics 70(3): 233-239, 2006.
3. Wali A, Ali G, John P, Lee K, Chishti MS, Leal SM, Ahmad W. Mapping of a Gene for Alopecia with Mental Retardation Syndrome (APMR3) on Chromosome 18q11.2-q12.2. Annals of Human Genetics 71(5): 570-577,2007.
4. Wali A, Chishti MS, Ayub M, Yasinzai M, Kafaitullah, Ali G, John P, Ahmad W. Localization of a novel autosomal recessive hypotrichosis locus (LAH3) to chromosome 13q14.11-q21.32. Clinical Genetics 72(1): 23-29,2007.