Melanocortin 1 receptor: what's red got to do with it?
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Animals↗
Biomedical subjects
J L Rees
Publications and source records attributed to J L Rees.
Medial unicompartmental arthroplasty after failed high tibial osteotomy.
Satisfactory selection criteria are essential for the successful outcome of unicompartmental knee arthroplasty (UCA). We report the frequency of revision of the Oxford medial unicompartmental arthroplasty in knees previously treated for anteromedial osteoarthritis by high tibial osteotomy (HTO). The combined results from three sources were used to allow statistical analysis of this uncommon subgroup. In the combined series of 631 knees (507 patients) which had medial unicompartmental replacement, 613 were primary procedures and 18 were for a failed HTO. The mean follow-up times of the two groups were similar (5.8 years and 5.4 years, respectively). At review, 19 (3.1%) of the primary procedures and five (27.8%) of those undertaken for a failed HTO had been revised to total knee replacement. Survival analysis revealed the ten-year cumulative survivals to be 96% and 66%, respectively. The log-rank comparison of these survivals revealed a highly significant difference (p < 0.0001). We recommend that the Oxford UCA should not be used in knees which have previously undergone an HTO.
Adult↗
Reconstruction does not reduce tibial translation in the cruciate-deficient knee an in vivo study.
We have assessed the effectiveness of reconstruction of the anterior cruciate ligament (ACL) in reducing functional tibial translation (TT). The gait of 11 ACL-deficient patients was studied using Vicon equipment before and after surgery. Measurements of the angle between the patellar tendon and the long axis of the tibia were obtained in order to calculate TT in the sagittal plane relative to the uninjured limb during standing and walking. Before surgery, patients did not show abnormal TT on the injured side, but after surgery significant anterior TT was found in the operated limb for every parameter of gait. Abnormal anterior TT occurring during activity does not seem to be reduced by reconstruction; rather, it increases. It may be that the increased translation results from relaxation of excess contraction of the hamstring muscles, since compensatory muscle activity no longer is required in a reconstructed knee. The reduction of TT may not be an appropriate objective in surgery on the ACL.
Adult↗
Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation.
Variants of the melanocortin 1 receptor (MC1R) gene are common in individuals with red hair and fair skin, but the relative contribution to these pigmentary traits in heterozygotes, homozygotes and compound heterozygotes for variants at this locus from the multiple alleles present in Caucasian populations is unclear. We have investigated 174 individuals from 11 large kindreds with a preponderance of red hair and an additional 99 unrelated redheads, for MC1R variants and have confirmed that red hair is usually inherited as a recessive characteristic with the R151C, R160W, D294H, R142H, 86insA and 537insC alleles at this locus. The V60L variant, which is common in the population may act as a partially penetrant recessive allele. These individuals plus 167 randomly ascertained Caucasians demonstrate that heterozygotes for two alleles, R151C and 537insC, have a significantly elevated risk of red hair. The shade of red hair frequently differs in heterozygotes from that in homozygotes/compound heterozygotes and there is also evidence for a heterozygote effect on beard hair colour, skin type and freckling. The data provide evidence for a dosage effect of MC1R variants on hair as well as skin colour.
Alleles↗
Melanocortin-1-receptor gene and sun sensitivity in individuals without red hair.
Susceptibility to sunburn, photoageing, and skin cancer is inversely related to an individual's ability to tan after sun exposure. We examined variants in the melanocortin-1-receptor (MC1R) gene in individuals from Ireland and the UK. We found evidence of an association between the degree of tanning after repeated sun exposure, and the number of variant alleles present. Heterozygotes were intermediate between wild-type individuals and those with two variant alleles. We suggest that MC1R gene status therefore determines sun sensitivity in people without red hair.
Adult↗
Evidence for variable selective pressures at MC1R.
It is widely assumed that genes that influence variation in skin and hair pigmentation are under selection. To date, the melanocortin 1 receptor (MC1R) is the only gene identified that explains substantial phenotypic variance in human pigmentation. Here we investigate MC1R polymorphism in several populations, for evidence of selection. We conclude that MC1R is under strong functional constraint in Africa, where any diversion from eumelanin production (black pigmentation) appears to be evolutionarily deleterious. Although many of the MC1R amino acid variants observed in non-African populations do affect MC1R function and contribute to high levels of MC1R diversity in Europeans, we found no evidence, in either the magnitude or the patterns of diversity, for its enhancement by selection; rather, our analyses show that levels of MC1R polymorphism simply reflect neutral expectations under relaxation of strong functional constraint outside Africa.
Africa↗
Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma.
Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by nail dystrophy, focal non-epidermolytic palmoplantar keratoderma (FNEPPK) and oral lesions. We have previously shown that mutations in keratin 16 (K16) cause fragility of specific epithelia resulting in phenotypes of PC-1 or FNEPPK alone. Here, we report 2 novel mutations in K16 causing distinct phenotypes. A heterozygous missense mutation (L124R) was detected in a kindred with PC-1. In a family where mild FNEPPK was the only phenotype, a 23 bp deletion and a separate 1 bp deletion downstream were found in exon 6: [1244-1266del; 1270delG]. At the protein level, these mutations remove 8 residues and substitute 2 residues in the helix termination motif (HTM) of the K16 polypeptide. The HTM sequence is conserved in all known intermediate filament proteins and for convenience, this complex mutation was designated deltaHTM. Transient expression of K16 cDNAs carrying either the L124R or the deltaHTM mutation in epithelial cell line PtK2 produced aggregation of the keratin cytoskeleton. However, the aggregates observed with the deltaHTM mutation were morphologically different and appeared to be less disruptive to the endogenous cytoskeleton. Therefore, loss of the HTM sequence may render this mutant K16 less capable of contributing to filament assembly and decrease its dominant-negative effect, resulting in the milder FNEPPK phenotype.
Base Sequence↗
The melanocortin 1 receptor (MC1R): more than just red hair.
The melanocortin 1 receptor, a seven pass transmembrane G protein coupled receptor, is a key control point in melanogenesis. Loss-of-function mutations at the MC1R are associated with a switch from eumelanin to phaeomelanin production, resulting in a red or yellow coat colour. Activating mutations, in animals at least, lead to enhanced eumelanin synthesis. In man, a number of loss-of-function mutations in the MC1R have been described. The majority of red-heads (red-haired persons) are compound heterozygotes or homozygotes for up to five frequent loss-of-function mutations. A minority of redheads are, however, only heterozygote. The MC1R is, therefore, a major determinant of sun sensitivity and a genetic risk factor for melanoma and non-melanoma skin cancer. Recent work suggests that the MC1R also shows a clear heterozygote effect on skin type, with up to 30% of the population harbouring loss-of-function mutations. Activating mutations of the MC1R in man have not been described. The MC1R is particularly informative and a tractable gene for studies of human evolution and migration. In particular, study of the MC1R may provide insights into the lightening of skin colour observed in most European populations. The world wide pattern of MC1R diversity is compatible with functional constraint operating in Africa, whereas the greater allelic diversity seen in non-African populations is consistent with neutral predictions rather than selection. Whether this conclusion is as a result of weakness in the statistical testing procedures applied, or whether it will be seen in other pigment genes will be of great interest for studies of human skin colour evolution.
Alleles↗
The temporal and spatial distribution of p21WAF expression in skin appendages.
p21WAF is a cyclin-dependent kinase inhibitor which is widely expressed in epidermal structures. Using a combination of double immunocytochemical staining and combined in situ hybridization, we show that there is a striking exclusivity between the expression of Ki67 and p21WAF in the hair matrix. Some cells that are Ki67-positive also express p53, but as they exit the cell cycle they assume p21WAF-positive/p53-negative status. By contrast, cells in the interfollicular epidermis of psoriatic lesions, in the sebaceous gland, and in the outer root sheath are p21WAF-positive/p53-positive but Ki67-negative. These results suggest that in some anatomical parts of the epidermis, p21WAF expression can accompany p53 expression, whereas in other parts, the expression of these markers is reciprocal, suggesting that other pathways may be controlling p21WAF expression. In order to define, functionally, the presence of p53-independent p21WAF expression in skin, we examined lesions of Bowen's disease in which both alleles of p53 were inactivated. p21WAF expression was still observed, confirming a role for p53-independent expression of p21WAF in human skin in vivo.
Bowen's Disease↗
Genetics, past and present, and the rise of systems dermatology.
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Dermatology↗
The spectrum of mitochondrial DNA deletions is a ubiquitous marker of ultraviolet radiation exposure in human skin.
We and colleagues have suggested that deletions of mitochondrial DNA may be useful as a biomarker of ultraviolet radiation exposure in skin. In this study using a southwestern approach involving monoclonal antibodies against thymine dimers we provide direct evidence for the presence of ultraviolet-induced damage in mitochondrial DNA purified from any nuclear DNA contamination. Previous studies have been limited, as they have focused on the frequency of a single mitochondrial DNA deletion. Therefore we have addressed the question of the spectrum of mitochondrial DNA deletions in skin and whether this can be used as an index of overall DNA damage. We have used a long polymerase chain reaction technique to determine the mitochondrial DNA deletion spectrum of almost the entire mitochondrial genome in 71 split skin samples in relation to sun exposure. There was a significant increase in the number of deletions with increasing ultraviolet exposure in the epidermis (Kruskal-Wallis test, p = 0.0015) but not the dermis (p = 0.6376). The findings in the epidermis are not confounded by any age-dependent increases in mitochondrial DNA deletions also detected by the long polymerase chain reaction technique. The large spectrum of deletions identified in our study highlights the ubiquitous nature and the high mutational load of mitochondrial DNA associated with ultraviolet exposure and chronologic aging. Compared with the detection of single deletions using competitive polymerase chain reaction, we show that long polymerase chain reaction is a sensitive technique and may therefore provide a more comprehensive, although not quantitative, index of overall mitochondrial DNA damage in skin.
Biomarkers↗
Genetic studies of the human melanocortin-1 receptor.
Genetic approaches have suggested a critical role for the melanocortin-1 receptor in the control of pigmentation. We showed that this gene is unusually polymorphic in European populations and that, of the many variants, three in particular appear to be associated with red hair or fair skin. Family studies suggest these are inherited as an autosomal recessive trait (or at least approximate to this in many families). To date all individuals with two of these three changes (homozygote or compound heterozygote) have red hair. Early functional studies are in keeping with defective signalling through MC1R. An interested and perhaps unexpected question relates to the evolutionary factors that have given rise to such variants. Two models can be proposed, that are based on multiple alleles with minor changes in function or genetic hitch-hicking.
Animals↗
Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair.
The melanocortin 1 receptor is a G-protein-coupled receptor that acts as a control point for control of the eumelanin/phaeomelanin ratio in mouse hair. MC1 receptor loss of function mutations lead to an increase in the ratio of phaeomelanin/eumelanin in many mammals resulting in yellow or red coat colours. We have previously shown that several common point mutations in the human MC1 receptor are overrepresented in North European redheads and in individuals with pale skin. In order to determine the functional significance of these changes we have carried out transfection and binding studies. Expression of the Val60Leu, Arg142His, Arg151Cys, Arg160Trp, and Asp294His receptors in COS 1 cells revealed that these receptors were unable to stimulate cAMP production as strongly as the wild type receptor in response to alpha-melanocyte-stimulating hormone stimulation. None of the mutant receptors displayed complete loss of alphaMSH binding, with only the Arg142His and Asp294His displaying a slight reduction in binding affinity.
Amino Acid Sequence↗
Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease.
Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.
Calcium-Transporting ATPases↗
Low frequency of genetic change in p53 immunopositive clones in human epidermis.
Sun-exposed skin of Caucasians harbors thousands of p53-mutated clones, which are clinically invisible. Using whole mount immunostaining for p53 or Ki67 antigens, p53 sequencing, and loss of heterozygosity analysis, we have further characterised these clones. Loss of heterozygosity for the alleles examined is uncommon with the exception of 9q, which occurred in 28.3% of the samples. P53 clones are more common and larger in individuals with basal cell carcinoma than in control subjects (p < 0.03). Loss of heterozygosity is also more common in clones from individuals with basal cell carcinoma than in clones from subjects without a history of basal cell carcinoma, as would be expected if both relate to ultraviolet radiation exposure. p53 sequencing of clones is in keeping with the mutagenic role of ultraviolet radiation. Surprisingly, skin found to harbor p53 clones showed no clusters of Ki67 positive cells, unlike the situation for actinic keratoses or basal cell carcinomas. These results show that in human skin p53 mutation is not directly associated with genomic instability or abnormal cell cycling; that the p53 immunopositive clones are either genetically distinct or precursors to other squamous cell lesions of skin; and that p53 immunopositive clones are early lesions, in that gross disturbance of proliferation has not already occurred.
Aged↗
Dowling Oration delivered at the Royal Society of Medicine, 18 February 1999. The importance of being red.
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Humans↗
Pruritus: more scratch than itch.
Itch is one of the major symptoms of skin disease although it remains poorly studied. Little is known about its mediators or the neurological processes involved in either the detection of an itch stimulus or the induction of the main response to itch, scratch. This lack of knowledge may be due to the subjective nature of the sensation itself and the related difficulties in quantifying it, and is compounded by the absence of a convincing animal model. Defining itch as that sensation which provokes the desire to scratch provides two approaches to measurement, that of itch itself, and the behavioural response, scratch. The measurement of itch itself traditionally involves the use of questionnaires or visual analogue scale, both of which rely on the dubious assumption that the subject is able to relate their experiences accurately. By contrast experimental induction of itch and measurement of areas of allokinesis around application sites may provide a more reliable and repeatable method of itch quantification. Recent advances in two areas that may prove relevant are discussed: new technological improvements in movement meters and compatible software; and some recently described animal models.
Humans↗
Management of equinus contractures of the ankle in haemophilia.
Equinus deformity has been a significant problem in haemophilia. It causes difficulties in walking and secondary problems in adjacent joints. There are a number of potential causes in haemophilia. A careful history, examination, and plain radiographs will determine the aetiology, which frequently is multifactorial. Hopefully, prophylactic factor replacement will reduce the incidence of such problems in the future. Prompt 'on demand' therapy will reduce the complications of articular and soft-tissue bleeds. Physiotherapy, splints, and orthotics will usually allow a full recovery of function and comfort. Rarely, surgical intervention is required to correct articular and/or musculo-tendinous problems. The choice of surgery depends upon the cause(s) of the deformity and should only be undertaken in experienced haemophilia units following careful counselling of the patient regarding the aims and nature of the operation and the patient's involvement in an effective rehabilitation programme.
Ankle↗