The Melanocortin-1 Receptor (MC1R) is a G-protein coupled receptor, which is responsible
for production of the darker eumelanin pigment and the tanning response. The MC1R gene
has many polymorphisms, some of which have been linked to variation in pigmentation
phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and
p.D294H alleles have been strongly associated with red hair, fair skin and increased skin
cancer risk. These red hair colour (RHC) variants are relatively well described and are
thought to result in altered receptor function, while still retaining varying levels of signaling
ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W
and p.D294H alleles were able to partially rescue this phenotype, leading to the question of
what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null
alleles in human populations, they have only been found in the heterozygous state until now.
We report here the first case of a homozygous MC1R null individual, phenotypic analysis
indicates that red hair and fair skin is found in the absence of MC1R function
RESULTS
Analysis of pigmentation characteristics in individuals genotyped for 9 common MC1R variants in a previous
study revealed the presence of a red haired individual wild type for all MC1R loci analysed (Beaumont, et al.,
2007). Complete MC1R sequence analysis identified that this individual was actually a compound heterozygote for
two rare insertions c.86_87insA (Figure 1A) and c.537_538insC (Figure 1B). The c.86_87insA occurs in the Nterminal region of MC1R and causes a frameshift that results in a premature stop codon 36 base pairs down stream
of the insertion (Figure 1C). The c.537_538insC frameshift occurs in the fourth transmembrane region of MC1R
and results in a premature stop codon 174 base pairs down stream (Figure 1C). The proband is thus essentially null
for MC1R as both frameshifts result in a truncated, ostensibly non-functional receptor. The probands immediate
family was also sequenced for MC1R, the sibling was found to be of wild type MC1R genotype, while the mother was heterozygous for the c.537_538insC and the father was heterozygous for c.86_87insA (Table 1), consistent
Source to see the tables: https://sci-hub.se/https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.20788
for production of the darker eumelanin pigment and the tanning response. The MC1R gene
has many polymorphisms, some of which have been linked to variation in pigmentation
phenotypes within human populations. In particular, the p.D84E, p.R151C, p.R160W and
p.D294H alleles have been strongly associated with red hair, fair skin and increased skin
cancer risk. These red hair colour (RHC) variants are relatively well described and are
thought to result in altered receptor function, while still retaining varying levels of signaling
ability in vitro. The mouse Mc1r null phenotype is yellow fur colour, the p.R151C, p.R160W
and p.D294H alleles were able to partially rescue this phenotype, leading to the question of
what the true null phenotype of MC1R would be in humans. Due to the rarity of MC1R null
alleles in human populations, they have only been found in the heterozygous state until now.
We report here the first case of a homozygous MC1R null individual, phenotypic analysis
indicates that red hair and fair skin is found in the absence of MC1R function
RESULTS
Analysis of pigmentation characteristics in individuals genotyped for 9 common MC1R variants in a previous
study revealed the presence of a red haired individual wild type for all MC1R loci analysed (Beaumont, et al.,
2007). Complete MC1R sequence analysis identified that this individual was actually a compound heterozygote for
two rare insertions c.86_87insA (Figure 1A) and c.537_538insC (Figure 1B). The c.86_87insA occurs in the Nterminal region of MC1R and causes a frameshift that results in a premature stop codon 36 base pairs down stream
of the insertion (Figure 1C). The c.537_538insC frameshift occurs in the fourth transmembrane region of MC1R
and results in a premature stop codon 174 base pairs down stream (Figure 1C). The proband is thus essentially null
for MC1R as both frameshifts result in a truncated, ostensibly non-functional receptor. The probands immediate
family was also sequenced for MC1R, the sibling was found to be of wild type MC1R genotype, while the mother was heterozygous for the c.537_538insC and the father was heterozygous for c.86_87insA (Table 1), consistent
Source to see the tables: https://sci-hub.se/https://onlinelibrary.wiley.com/doi/abs/10.1002/humu.20788