Four novel variants in MC1R in red-haired South African individuals of European descent: S83P, Y152X, A171D, P256S

Abstract

Skin, hair and eye pigmentation is a polygenic multifactorial trait determined by the cumulative effects of multiple genetic variants and environmental factors. MC1R is one of the genes involved in pigmentation, and has been implicated in the red hair and pale skin trait in human Caucasoid individuals. This study was undertaken to investigate variants in the MC1R gene in Caucasoid individuals in South Africa, who are of European decent. Seven unrelated individuals were studied, all of whom were found to be either homozygous for a single mutation or compound heterozygous for two different mutations. We report four novel MC1R missense mutations: S83P, Y152X, A171D and P256S. This study supports the view that two mutations are necessary, but not necessarily sufficient, to give rise to the red hair and pale skin phenotype

Novel MC1R variants in Ligurian melanoma patients and controls

“…Most subjects were found to be either compound heterozygotes or homozygotes for known R variants (p.R142H, p.R151C, p.R160W, p.D294H), 1 was a compound heterozygote carrying p.I155T/p.R151C (strawberry blonde hair/hazel eyes/phototype II) and 3 subjects were heterozygotes. Along with these variants which are known to lead to loss of function and for acting recessively, we also found the c.456C>A (p.Y152X), which has been recently described and leads to receptor truncation and presumably loss of function (John and Ramsay, 2002), and the novel variant c.520_523delGTC (deletion in frame of the 3 nucleotides). Two out of 17 individuals had redhaired first-degree relatives.…”

“…Variant p.S83L is at a site that has already been described (John and Ramsay, 2002) but with different amino acid substitutions. It occurs in the second transmembrane region, which apparently plays a key role in the molecule as substitutions associated with red hair and fair skin in humans are found in this part of the molecule in the animal model (Marklund et al, 1996).…”

Comparative oncology: what dogs and other species can teach us about humans with cancer

“…In humans, KITLG is not associated with cancer risk, although rare germline KIT mutations have been associated with familial gastrointestinal stromal tumours (GIST), a type of gastrointestinal sarcoma [44]. Interestingly, there is precedent for the role of MC1R as a modifier of disease, as germline MC1R variants in humans affect pigmentation [45,46] and seemingly function as genomic modifiers for several human diseases [47][48][49][50][51], in one study conferring risk for BRAF-mutant melanoma [52].…”

MC1R gene variants involvement in human OCA phenotype

“…The partial loss-of-function mutations in the MC1R gene are most common among individuals of European ancestry with red or blond hair, freckles, light-colored skin that tans poorly and has an increased sensitivity to sun exposure [62][63][64][65]. From evolutionary point of view, it is important that human migration out of Africa to areas of limited sun exposure, leads to selection for functionally relevant variants of pigmentation genes, including MC1R in Europeans [66].…”