POSTER NO: 400

Severity of Monilethrix associated with a novel promoter polymorphism and the known pathogenic mutation in the helix termination motif of the hair cortex keratin gene, hHb6, in two Indian families

¹Narendra K. Bairwa, ²Sujay Khandpurkar, ¹Dheeraj Malhotra, ¹Anjana Saha, ²B.S.N. Reddy, ¹R. Bamezai
¹Human Genetics Section, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India, ²Department of Dermatology and STD, Maulana Azad Medical College, LNJP, New Delhi, India

Monilethrix is a rare autosomal dominant hair defect with variable expression, characterized by hair fragility and follicular hyperkeratosis. Pathogenic mutations in the human basic hair keratin genes, hHb1 and hHb6, have recently been reported in this disease. The defect lies in the synthesis, assembly and stabilization of keratin intermediate filament-matrix complex due to mutations in hHb6 and hHb1. The members of basic keratin gene family are present on chromosome 12q13. And, the mutations reported in diseased condition are restricted to helix initiation motif and the helix termination motif, of hHb6 and hHb1 genes. The severity of disease and hair dystrophy varies in monilethrix individuals inspite of the same mutational background. The reasons for this are not clear in the existing information in literature. Monilethrix cases of Indian origin have not been characterized for such mutations till date. Here, we report the cases studied in two different families for hHb6 mutation status. The level of severity in hair dystrophy in association with the mutation in the helix termination motif in the presence or absence of the promoter polymorphism of hHb6 gene is also evaluated to account for the less or more severe forms of the disease. Incidentally, there are no reports available for the status of the promoter and intron regions of this gene in the disease condition. The study was designed to study the clinical severity and hair dystrophy in association with the helix termination motif mutation and promoter polymorphism in two Indian monilethrix families. Here in this study, two unrelated families with 22 individuals were clinically diagnosed with monilethrix in 15 of its members. Clinical and microscopic abnormalities of the hair were recorded in all patients. Electron microscopy of the hair shaft was performed in both affected and unaffected members and compared. In order to investigate the pathogenic mutation in keratin gene, the gene segment encoding the Promoter and helix termination motif region of keratin hHb6 were PCR amplified and subjected to SSCP. The variant bands obtained were cloned and sequenced. Both families showed clinically diverse disease patterns, with 9 members (age group 6 months-65 years) across 3 generations affected in the first family, the Family A and 6 individuals (age group 1.5 years-35 years) across 2 generations affected in the second family, the Family B. The family A showed only scalp hair involvement while in the family B, the defect was present in all the hairy sites. Electron microscopy revealed abnormalities in the cuticle, cortex and inner root sheath of the hair. We observed an association of the severity of disease and hair dystrophy with disease causing mutation, E413K and a novel promoter polymorphism of hHB6 gene in patients in both the families. We also detected a novel polymorphism in intron-7 of hHB6 gene. Initial observation indicated that both E413K and promoter polymorphism when present together contributed to the severity of the disease, an observation not reported earlier.