Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin

Abstract

Abstract(1) Background-Atrichia with papular lesions (APL) is a rare autosomal recessive form of inherited alopecia. Affected individuals present with a distinct pattern of total hair loss on the scalp, axilla and body shortly after birth and are essentially devoid of eyelashes and eyebrows. This form of hair loss is irreversible and the histology is consistent with an absence of mature hair follicles. In addition to total atrichia, APL patients also present with papules and follicular cysts filled with cornified material. Mutations in the Hairless (HR) gene have been shown to underlie APL.(2) Objective-Here, we studied five unrelated large Pakistani families with clinical manifestations of APL.(3) Methods-Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis.(4) Results-DNA sequencing of the HR gene in APL patients revealed three novel nonsense mutations in five unrelated families. All affected individuals were homozygous for a nonsense mutation due to C-to-T transitions at different positions in the amino acid sequence. Two families carry the mutation Q323X (CAG-TAG) in exon 3, two families harbor the mutation Q502X (CAG-TAG) in exon 6, and one family had a mutation at R940X (CGA-TGA) in exon 14. Haplotype analysis revealed that all affected individuals of both APL1 and APL16 families were homozygous for the same haplotype, and likewise, the mutation in families APL2 and APL19 was on the the same haplotype.(5) Conclusions-We report three novel nonsense mutations in the HR gene in APL. Two of the newly identified mutations, Q323X and Q502X, were found to be shared between unrelated families and marker analysis confirmed an identical homozygous haplotype for APL1 and APL16, and for APL2 and APL19. These findings suggest that Q323X and Q502X did not arise independently, but instead appear to have been propagated in the population. Collectively, these findings contribute further evidence for the involvement of hairless mutations in papular atrichia.

Atrichia with Papular Lesions in a Chinese Family Caused by Novel Compound Heterozygous Mutations and Literature Review

“…On the contrary, it is intriguing that the recurrent mutations p.P1157R, p.Q323X and Q502X in 6 unrelated Pakistani families separately verified to have similar haplotype generated almost the same phenotypes [26,27]. Available evidence indicates that the common mutation 3434delC does not probably share an ancestry considering the number of papular lesions distinct from each Arab family [28,29]. However, given the relatively restricted Arab geographical region and clinical manifestations, it is highly reasonable to speculate that the hot mutation 2147delC is a ‘founder' mutation [30,31], which would be certified by haplotype analysis.…”

The Effect of Inbreeding on the Distribution of Compound Heterozygotes: A Lesson from Lipase H Mutations in Autosomal Recessive Woolly Hair/Hypotrichosis

“…Finally, direct sequencing of candidate genes leads to identification of the causative gene. By deploying this strategy, we have previously analyzed many consanguineous Pakistani families with autosomal recessive hair and nail disorders and have successfully identified homozygous mutations in causative genes, such as HR [1][2][3] , DSG4 [4][5][6] , RSPO4 [7,8] , P2RY5 [9,10] , and LIPH [11] .…”

Congenital atrichia associated with an uncommon mutation of HR gene

“…6 Therefore our case is the second reporting such a variant, but with the distinctive feature of absence of papular lesions, so far in any of the affected siblings. This finding, in accordance with other studies, 2,3,5 emphasizes the difficulty to establish a strict correlation between HR genotyping and the phenotype.…”