Genetic Mapping of Genes Causing Human Hereditary Alopecias and Ectodermal Dysplasias

Abstract

Hereditary alopecias and ectodermal dysplasias are genetically heterogeneous groups of congenital disorders involving abnormalities in ectodermal appendages (hair, nail, teeth, sweat glands). These hereditary disorders may occur either as an isolated condition or associated with defects in other organ/organ systems. Over the past few years, investigations into molecular basis of these genetic disorders have yielded insights into the functional pathways and mechanisms involved in biology of skin appendages. The present study deals with clinical and molecular characterization of fifteen consanguineous families segregating disorders of hairs and ectodermal dysplasias. In addition, five candidate genes were screened in three other families exhibiting alopecia and mental retardation (APMR) syndrome. Autosomal recessive form of isolated hypotrichosis was identified in six families (A- F). Sequence analysis of Lipase H (LIPH) gene, mapped on chromosome 3q27, identified a novel splice-site mutation (c.629-1G>C) in family A, and two recurrent variants (c.659-660delTA [p.Ile220Argfs*25]; c.322T > C [p.Trp108Arg]) in three families (B-D). Four other families (G-J) demonstrated syndromic forms of hair loss disorders including juvenile macular dystrophy (HJMD), (APMR) and Woodhouse- Sakati syndrome (WSS). Two of these families, showing different phenotypes, mapped on chromosome 2q22.3-q31.1. In one of the family (J), sequence analysis identified a novel splice site mutation (c.321+1G>A) in the gene C2orf37. Five other families, presented in the dissertation, exhibited different forms of ectodermal dysplasias including a novel type with hypotrichosis, nail dystrophy and reticulate pattern of hyperpigmentation in family N. SNP based genome wide analysis mapped the phenotype on chromosome 18p11.32-p11.31. However, screening 17 candidate genes, located within the linkage interval, failed to detect any potential sequence variant. In family O with pure hair and nail ectodermal dysplasia (PHNED), a novel duplication mutation (c.200-203dupGCCA [p.His68Glnfs*84]) was detected in the recently reported gene HOXC13, mapped on chromosome 12p11.1-q21.1. In a large family (R), segregating nail and bone deformity (brachydactyly type B1) in Genetic Mapping of Genes Causing Human Hereditary Alopecias and Ectodermal Dysplasias XVIIAbstract autosomal dominant fashion, screening the gene ROR2 revealed a previously known nonsense mutation (c.2278C>T [p.Q760*]). Overall, the knowledge derived from identification of different disease causing gene variants and locus enhances our understanding of genetic basis of these rare and diverse inherited skin disorders in Pakistani population and adds data to the growing mutation database for selected genetic disorders. These are the initial steps taken to unveil the molecular pathways involved in the pathophysiologies of the disorders and gives incentives for further studies into genotype-phenotype correlation, gene functional studies and for prognostic implications in pre-natal diagnosis and clinical management of the disease. The work presented in the dissertation contributed in publishing the following articles. 1. Habib R, Ansar M, Shahid M, Ali G, Ahmad W, Betz RC (2013). A Novel Locus for Ectodermal Dysplasia of Hair, Nail and Skin pigmentation anomalies Maps to Chromosome 18p11.32–11.31. (Submitted to Clinical Genetic). 2. Ali RH, Habib R, Ud-Din N, Khan MN, Ansar M, Ahmad W (2013). Novel mutations in the gene HOXC13 underlying pure hair and nail ectodermal dysplasia in consanguineous families. British Journal of Dermatology (In Press) (Co first author). 3. Habib R, Amin-Ud-Din M, Ahmad W (2013). A nonsense mutation in the gene ROR2 underlying autosomal dominant brachydactyly type B. Clinical Dysmorphology 22: 47-50. 4. Habib R, Basit S, Khan S, Khan MN, Ahmad W (2011). A novel splice site mutation in gene C2orf37 underlying Woodhouse-Sakati syndrome (WSS) in a consanguineous family of Pakistani origin. Gene 490: 26-31. 5. Khan S, Habib R, Mir H, Umm-e-Kalsoom, Naz G, Ayub M, Shafique S, Yamin T, Ali N, Basit S, Wasif N, Kamran-ul-Hassan Naqvi S, Ali G, Wali A, Ansar M, Ahmad W (2011). Mutations in the LPAR6 and LIPH genes underlie autosomal recessive hypotrichosis/woolly hair in 17 consanguineous families from Pakistan. Clinical and Experimental Dermatology 36: 652-654. Genetic Mapping of Genes Causing Human Hereditary Alopecias and Ectodermal Dysplasias XVIIIAbstract 6. Kalsoom UE, Habib R, Khan B, Ali G, Ali N, Ansar M, Ahmad W (2010). Mutations in lipase H gene underlie autosomal recessive hypotrichosis in five Pakistani families. Acta Dermatological Venereology 90: 93-94.