Atrichia with Papular Lesions in Five Consanguineous Palestinian Families Caused by a Single Base Pair Deletion Mutation within the Human Hairless Gene

Abstract

Background: Hair loss has significant psychological and social impacts on individuals affected with the disease and can cause considerable anxiety among family members. Atrichia with Papular Lesions (APL; Mendelian Inheritance in Man no. 209500) is an example of rare genetic hair loss disease that is inherited in an autosomal recessive pattern. It is characterized by complete irreversible hair loss on the scalp and entire body during the first months of life with widespread papules (keratin-filled cysts) on the skin that appear within the first years of life. This disease spreads in consanguineous families with high fertility rate especially residents in small geographically isolated regions. Molecular analysis revealed mutations in the hairless gene (HR) on chromosome 8p12 which are considered to be the main cause of this genetic disorder. This gene encodes a putative transcription factor with a single zinc-finger domain of 1189 amino acids and is highly expressed in brain and skin. The purpose of our study is to discover the genetic causes of APL in a number of Palestinian families suffering from this disease. Methods: To find the causative mutation for APL, five Palestinian families with the disease were recruited for our study. Linkage Exclusion Analysis was used at the beginning of the study to exclude this locus as the cause of the disease. HR gene could not be excluded in our families thus we performed Sanger Sequencing to identify the causative mutation in this gene. Sanger sequencing was also used to test the genotype phenotype segregation within the families and to determine the carrier frequency of this mutation in 100 healthy controls. IV Results: Sanger sequencing results revealed a single base pair deletion mutation at position 2147 (2147delC), which leads to a frameshift and premature termination codon. This stop codon is 544 bps downstream in exon 12. This deletion of C causes a frameshift mutation that changes the reading frame (P716Q fS*186). Also, Sanger sequencing results showed that this mutation in HR gene segregates perfectly in a recessive mode of inheritance in all families. This mutation was not detected among 100 healthy Palestinian controls. Conclusion: Our study reports a single base pair deletion in exon 9 of HR gene in a homozygous form in all affected members of five Palestinian families with Congenital Atrichia. Mutations in this gene were also discovered to cause APL in people from different ethnic backgrounds. Key words: Atrichia with Papular Lesions (APL), Linkage Exclusion Analysis, Sanger Sequencing, Alopecia, HR gene