Skin type, melanoma, and melanocortin 1 receptor variants.
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Hair Color↗
Biomedical subjects
J L Rees
Publications and source records attributed to J L Rees.
Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: implications for protein structure and clinical phenotype.
Monilethrix is an hereditary hair dystrophy recently shown to be due to mutations in the helix termination motif of two type II (basic) human hair keratin genes, hHb1 and hHb6. It has been suggested that mutation in hHb1 produces a less severe phenotype. We have studied hair keratin genes and clinical features in 18 unrelated pedigrees of monilethrix from Germany, Scotland, Northern Ireland, and Portugal, in 13 of which mutations have not previously been identified. By examining the rod domains of hHb1, hHb3 and hHb6, we have identified mutations in nine of the new pedigrees. We again found the glutamine-lysine substitution (E413K) in the helix termination motif of hHb6 in two families, and in another, the corresponding E413K substitution in the hHb1 gene. In four families a similar substitution E402K was present in a nearby residue. In addition two novel mutations within the helix initiation motif of hHb6 were found in Scottish and Portuguese cases, in whom the same highly conserved asparagine residue N114 was mutated to histidine (N114H) or aspartic acid (N114D) residues, respectively. In four other monilethrix pedigrees mutations in these domains of hHb1, hHb3, and hHb6 were not found. The mutations identified predict a variety of possible structural consequences for the keratin molecule. A comparison of clinical features and severity between cases with hHb1 and hHb6 mutations does not suggest distinct effects on phenotype, with the possible exception of nail dystrophy, commoner with hHb1 defects. Other factors are required to explain the marked variation in clinical severity within and between cases.
Amino Acid Sequence↗
ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class.
Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.
Calcium-Transporting ATPases↗
Pigmentation, melanocortins and red hair.
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Animals↗
How realistic is cutaneous gene therapy?
Recent progress with innovative, experimental gene therapy approaches in animals, and recent improvements in our understanding and manipulation of stem cells, gene expression and gene delivery systems, have raised plenty of hopes in essentially all branches of clinical medicine that hitherto untreatable or poorly manageable diseases will soon become amenable to treatment. Few other organ systems have received such enthusiastic reviews in recent years as to the chances and prospects of gene therapy as the skin, with its excellent accessibility and its pools of--seemingly--readily manipulated epithelial stem cells (cf. Cotsarelis et al., Exp Dermatol 1999: 8: 80-88). However, as in other sectors of clinical medicine, the actual implementation of general gene therapy strategies in clinical practice has been faced with a range of serious difficulties (cf. Smith, Lancet 1999: 354 (suppl 1): 1-4; Lattime & Gerson (eds.), Gene Therapy of Cancer, Academic Press, San Diego, 1999). Thus, it is critically important to carefully distinguish unfounded hype from justified hope in this embryonal area of dermatologic therapy, to discuss in detail what can be realistically expected from cutaneous gene therapy approaches in the next few years, and importantly, what kind of promises should not be made to our patients at this time.
Animals↗
Point mutation in the helix termination peptide (HTP) of human type II hair keratin hHb6 causes monilethrix in five families.
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Alopecia↗
Mosaic atopic eczema cured by autotransplantation?
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Adolescent↗
Prognostic significance of allelic losses in primary melanoma.
Loss of genetic material, including loss of loci on chromosome arms 6q, 9p, and 10q, occurs frequently in cutaneous melanoma but infrequently in benign melanocytic nevi or other melanocytic lesions, suggesting that these genetic alterations are important in the development and progression of melanoma. To examine whether allelic loss is of prognostic importance in melanoma, disease-free survival was related to loss of heterozygosity on 6q, 9p and 10q in 83 individuals with sporadic primary cutaneous melanoma. Loss of chromosome arms 6q and 10q were each significantly associated with a poorer clinical outcome (P=0.013 and P=0.001 respectively). In a subgroup of 41 subjects whose primary tumours were allelotyped, the fractional allelic loss (FAL) at 39 autosomal arms also significantly correlated with disease-free survival (P=0.013), with an increase in FAL associated with a poorer outcome; this association remained significant when controlled for tumour thickness (P=0.035). In addition, a greater proportion of cells were immunopositive for Ki67 antigen, p53 and p21WAF1 protein in the primary melanomas than in the benign melanocytic nevi, however, only p53 over-expression was significantly associated with improved survival (P=0.041).
Alleles↗
A trichilemmal carcinoma arising from a proliferating trichilemmal cyst: the loss of the wild-type p53 is a critical event in malignant transformation.
The genetic events responsible for tumor progression may be defined by careful analysis of genetic changes in well-chosen tumors which contain distinct cell populations representing each stage of progression. Here we report a case of a trichilemmal carcinoma arising in the wall of a proliferating trichilemmal cyst (PTC). DNA was isolated from microdissected areas of the PTC and the carcinoma respectively, and PCR-based microsatellite loss of heterozygosity (LOH) analysis as well as p53 gene sequencing performed. A CGA to TGA nonsense mutation at codon 306 in exon 8 of the p53 gene was found in both samples. LOH analysis showed that the PTC retained chromosome arm 17p (where the p53 gene resides), whereas the carcinoma was associated with the loss of this allele. All the other loci examined were retained including 3p, 9q, 13q and 17q in both tumor parts. The results confirm a common clonal origin of the PTC and the trichilemmal carcinoma, and strongly suggest that the complete loss of the wild-type p53 is a critical event responsible for malignant transformation in this particular case.
Aged↗
Mitochondrial DNA deletions in human skin reflect photo- rather than chronologic aging.
We have examined the use of mitochondrial DNA (mtDNA) as a molecular marker to study the relation between chronologic aging and photoageing in human skin. Using a 3-primer quantitative polymerase chain reaction method we have studied changes in the ratio of the 4977 bp deleted to wild-type mtDNA in relation to sun exposure and chronologic age of human skin. Based on previous studies, samples showing greater than 1% deleted mtDNA were classed as abnormal. There was a significant increase in the incidence of high levels (i.e., >1%) of the 4977 bp deleted mtDNA in sun-exposed sites (27%, 27 of 100) compared with sun-protected sites (1.1%, one of 90) (Fisher's exact test, p < 0.0001). There appeared to be no relation between the frequency of the mtDNA deletion and age. Analysis of split skin samples showed that most deletions (93%, n = 27) were confined to the dermal rather than the epidermal component, and in keeping with this deletions were found in three of six primary cultures of fibroblasts from sun-exposed sites. Deletions were not seen in the epidermal component of several epidermal tumors nor were deletions seen in fibroblasts cultured from an individual with Werner's syndrome. We propose that deletions or mutations of mitochondrial DNA may be useful as a marker of cumulative ultraviolet radiation exposure.
Adolescent↗
Melanocortin 1 receptor variants in an Irish population.
The identification of an association between variants in the human melanocortin 1 receptor (MC1R) gene and red hair and fair skin, as well as the relation between variants of this gene and coat color in animals, suggests that the MC1R is an integral control point in the normal pigmentation phenotype. In order to further define the contribution of MC1R variants to pigmentation in a normal population, we have looked for alterations in this gene in series of individuals from a general Irish population, in whom there is a preponderance of individuals with fair skin type. Seventy-five per cent contained a variant in the MC1R gene, with 30% containing two variants. The Arg151Cys, Arg160Trp, and Asp294His variants were significantly associated with red hair (p = 0.0015, p < 0.001, and p < 0.005, respectively). Importantly, no individuals harboring two of these three variants did not have red hair, although some red-haired individuals only showed one alteration. The same three variants were also over-represented in individuals with light skin type as assessed using a modified Fitzpatrick scale. Despite these associations many subjects with dark hair/darker skin type harbored MC1R variants, but there was no evidence of any particular association of variants with the darker phenotype. The Asp294His variant was similarly associated with red hair in a Dutch population, but was infrequent in red-headed subjects from Sweden. The Asp294His variant was also significantly associated with nonmelanoma skin cancer in a U.K. population. The results show that the Arg151Cys, Arg160Trp, and Asp294His variants are of key significance in determining the pigmentary phenotype and response to ultraviolet radiation, and suggest that in many cases the red-haired component and in some cases fair skin type are inherited as a Mendelian recessive.
Adult↗
A mutational hotspot in the 2B domain of human hair basic keratin 6 (hHb6) in monilethrix patients.
Monilethrix is an inherited hair dystrophy in which affected, fragile, hairs have an unique beaded morphology. Ultrastructural studies suggest a defect in filament structure in the cortex of the hair, and the hard keratins of hair and nail are thus candidate genes. In several families with autosomal dominant monilethrix, the disorder has been linked to the type II keratin gene cluster at chromosome 12q13. Recently, causative mutations in the critical helix termination motif in the 2B domain of the human hair basic keratin 6 (hHb6) have been identified. We now report the results of sequencing this domain in 13 unrelated families or cases with monilethrix. Five of the 13 had the same mutation as previously found, a G to A transversion leading to a lysine for glutamic acid substitution (E413K) in the 2B domain (residue 117 of the 2B helix) of hHb6. The mutation was confirmed by a restriction fragment length polymorphism assay developed for this purpose, and, as this mutation is evidently a common cause of the syndrome, for use in screening other cases. In eight families or cases, however, including three in whom linkage data are consistent with a defect at the type II keratin locus, no mutation was found in this domain of hHb6.
Family Health↗
Refined genetic mapping of the darier locus to a <1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region.
Darier disease (DD) (MIM 124200) is an autosomal dominant skin disorder characterized by loss of adhesion between epidermal cells and by abnormal keratinization. We present linkage analysis showing, in four families, key recombination events that refine the location of the DD locus on chromosome 12q23-24.1 to a region of <1 cM. We have constructed a YAC/P1 artificial chromosome (PAC)/bacterial artificial chromosome (BAC)-based physical map that encompasses this refined DD region. The map consists of 35 YAC, 69 PAC, 16 BAC, and 2 cosmid clones that were ordered by mapping 54 anonymous sequence-tagged sites. The critical region is estimated to be 2.4 Mb in size, with an average marker resolution of 37.5 kb. The refinement of the critical interval excludes the ALDH2, RPL6, PTPN11, and OAS genes, as well as seven expressed sequence tags (ESTs) previously mapped in the DD region. The three known genes (ATP2A2, PPP1CC, and SCA2) and the 10 ESTs mapped within the critical region are not obvious candidates for the DD gene. Therefore, this detailed integrated physical, genetic, and partial transcript map provides an important resource for the isolation of the DD gene and, possibly, other disease genes.
Chromosome Mapping↗
p53 mutation spectrum in Japanese Bowen's disease suggests a role for mutagens other than ultraviolet light.
The Japanese have a much lower incidence of nonmelanoma skin cancers (NMSCs) than Caucasians, presumably due in part to their skin type conferring relative protection from ultraviolet light radiation (UVR). To examine the contribution of environmental or endogenous mutagens other than UVR, which are expected to be relatively more important to the overall burden of NMSCs in the Japanese, we directly sequenced exons 5-8 of the p53 tumour suppressor gene in 29 Japanese patients with Bowen's disease, an in situ squamous-cell carcinoma of the skin. We found 9 mutations, including two CC:GG to TT:AA tandem transitions (presumably related to UVR), 3 transversions and 4 frameshift mutations. The mutational spectrum seen in our study contrasts with that we previously found in Bowen's disease from a Caucasian population, in keeping with a different aetiology for Bowen's disease in the respective populations. The unexpectedly high prevalence of frameshift mutations suggests that environmental mutagens other than UVR that preferentially induce deletion or insertion mutations may play an important role in the tumorigenesis of Japanese Bowen's disease, and warrants further investigation.
Aged↗
A comparative study of treadmill tests and heel raising exercise for peripheral arterial disease.
OBJECTIVES: This two part study validated a 1 min treadmill exercise test and compared this with simple heel raising exercise. METHODS: In an initial study of 24 claudicants (aged 43-79, median 63 years), ankle pressures were measured immediately after repeated treadmill exercises: for 1 min, until onset of claudication, and until maximum tolerated walking distance. Absolute value, fall and percent change in pressures were calculated. The results of this part of the study were then used as a "gold standard" for comparison with 30 s of heel raising and treadmill exercise. This second stage was performed on 21 symptomatic limbs (14 claudicants aged 42-73, median 69 years). RESULTS: Variability was least for pressures expressed as percent change after 1 min of exercise. The paired t-test revealed a significant correlation between the two methods of exercise (p < 0.05). CONCLUSION: Heel raising produced changes in ankle pressure which correlated well with those induced by treadmill exercise. We recommend the use of simple heel raising when a stress test is required to diagnose lower limb arterial insufficiency in the outpatient clinic.
Aged↗
Low frequency of allelic loss in skin tumours from immunosuppressed individuals.
Organ transplant recipients receiving immunosuppression show a dramatically increased risk of non-melanoma skin cancer. The cause of this increase is not known. We report that the rate of loss of heterozygosity (at all the loci we examined) was significantly lower in tumours from immunosuppressed individuals than in tumours from immunocompetent subjects [20 out of 148 (14%) vs 157 out of 428 (37%); P< 0.0001]. These results suggest that tumours in immunosuppressed individuals have a different molecular pathogenesis.
Alleles↗
Melanocortin receptors, red hair, and skin cancer.
Cutaneous pigmentation is a major determinant of the cutaneous response to ultraviolet radiation, and consequently of the risk of developing skin cancer. Over the past 10 years, several genes involved in melanogenesis have been identified, including the melanocortin 1 receptor gene. Recent work on the melanocortin 1 receptor suggests that it is a key player in determining whether eumelanin or pheomelanin is predominantly produced both in vitro and in vivo. In the mouse, variants of this receptor, which differ in their ability to activate adenylyl cyclase, are associated with different coat colors. In humans, melanocortin 1 receptor variants are associated with red hair and fair skin, and work in progress from our laboratory suggests that certain melanocortin 1 receptor variants may preferentially be associated with hair color rather than skin type. In addition, melanocortin 1 receptor variants are a risk factor, possibly independent of skin type, for melanoma susceptibility.
Animals↗
Deletion mapping of chromosome 3p and 13q and preliminary analysis of the FHIT gene in human nonmelanoma skin cancer.
Loss of heterozygosity of chromosomes 3p and 13q occurs frequently in human cutaneous squamous cell neoplasms, suggesting the presence of one or more tumor suppressor genes on these chromosome arms that may be involved in the pathogenesis of this tumor type. To date there is no clear evidence in cutaneous tumors where these putative genes are located. In this study we have analyzed 20 squamous cell neoplasms that show allelic loss at chromosome 13q, and 22 squamous cell neoplasms that show allelic loss at chromosome 3p, in an attempt to define the smallest area of deletion. One commonly deleted region was identified on chromosome 13 that centred around 13q13, and two commonly deleted regions were identified on chromosome 3 that mapped to 3p24-pter and 3p12-p14.1. Our findings suggest the presence of at least one tumor suppressor gene on chromosome 13 and two tumor suppressor genes on chromosome 3p that may be involved in the progression of these neoplasms. Deletions within the Fragile Histidine Triad gene, located at 3p14.2, have been reported in several tumors, leading to the suggestion that this gene is involved in tumor development. To evaluate the role of the Fragile Histidine Triad gene in nonmelanoma skin cancer, we have used reverse transcriptase polymerase chain reaction analysis to screen for deletions in 16 tumors (five basal cell carcinomas, five squamous cell carcinomas, five actinic keratoses, and one case of Bowen's disease) and HaCaT and A431 cell lines. A normal transcript was found to be expressed in 14 of 16 tumors and both cell lines. This suggests that the Fragile Histidine Triad gene is not a common target for deletion in Bowen's disease and the cell lines HaCaT and A431.
Acid Anhydride Hydrolases↗