Deepak Kashyap, Srashti Jyoti Agrawal, Meenakshisundaram Karthikeyan, Disha Biradar, Eerapagula Ramesh, Krithika Subramanian, Lomous Kumar, Urgyan Chorol, Audditiya Bandopadhyay, A. Vasanthakumar, Nagarjuna Pasupuleti, Tamilselvan Jayavelu, Ajay K. Mahato, Periyasamy Govindaraj, Gyaneshwer Chaubey, Bratati Kahali, Vivek T. Natarajan, Kumarasamy Thangaraj
The melanocortin 1 receptor (MC1R) is one of the fundamental proteins regulating skin and hair color in mammals. In India, the red hair color (RHC) phenotype is extremely rare. We analyzed MC1R and identified an ultra-rare pathogenic variant, c.872C>A (p.Ala291Asp), that is responsible for the RHC phenotype in an Indian child. Further, we screened the complete coding region of MC1R in a total of 11,021 individuals, representing 91 distinct Indian populations across India, and found a total of 21 novel or ultra-rare variants. In silico, in vitro, and zebrafish-based functional analysis showed that c.742G>T (p.Gly248Cys) and p.Ala291Asp variants lead to loss-of-function (LoF) effects. The distribution of some of these variants differed significantly among Indian populations. One of them is MC1R c.-226A>T (rs3212363), which is significantly associated with lighter skin pigmentation in the Bodh population inhabited in Ladakh. On average, TT homozygotes were 8.46 melanin units lighter compared with AA homozygotes (95% confidence interval [CI]: 3.211 to 13.72; adjusted p = 0.0005). Our study identifies and functionally validates ultra-rare MC1R variants as potential causes of RHC phenotype in Indians.