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Biomedical subjects

C S Munro

Publications and source records attributed to C S Munro.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mutant loricrin is not crosslinked into the cornified cell envelope but is translocated into the nucleus in loricrin keratoderma.

Loricrin is a major constituent of the epidermal cornified cell envelope. We have recently identified heterozygous loricrin gene mutations in two dominantly inherited skin diseases, the ichthyotic variant of Vohwinkel syndrome and progressive symmetric erythrokeratoderma, collectively termed loricrin keratoderma. In order to see whether the mutant loricrin molecules predicted by DNA sequencing are expressed in vivo and to define their pathologic effects, we raised antibodies against synthetic peptides corresponding to the mutated sequences of loricrin. Immunoblotting of horny cell extracts from loricrin keratoderma patients showed specific bands for mutant loricrin. Immunohistochemistry of loricrin keratoderma skin biopsies showed positive immunoreactivity to the mutant loricrin antibodies in the nuclei of differentiated epidermal keratinocytes. The immunostaining was localized to the nucleoli of the lower granular cell layer. As keratinocyte differentiation progressed the immunoreactivity moved gradually into the nucleoplasm leaving nucleoli mostly nonimmunoreactive. No substantial staining was observed along the cornified cell envelope. This study confirmed that mutant loricrin was expressed in the loricrin keratoderma skin. Mutant loricrin, as a dominant negative disrupter, is not likely to affect cornified cell envelope crosslinking directly, but seems to interfere with nuclear/nucleolar functions of differentiating keratinocytes. In addition, detection of the mutant loricrin in scraped horny layer could provide a simple noninvasive screening test for loricrin keratoderma. J Invest Dermatol 115:1088-1094 2000

Cell Nucleolus↗
PubMed1999

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↗
PubMed1999

The value of in-patient dermatology: a survey of in-patients in Scotland and Northern England.

Dermatology in-patient units are frequently threatened with reduction or closure, yet there are few objective data regarding the nature and use of in-patient management with which to assess their value. We have surveyed 300 patients admitted during March 1997 to dermatology units throughout Scotland and Northern England, to establish their clinical and social profile, and the outcome of admission. All departments provided phototherapy and out-patient treatment services, and 84% of those admitted lived within an hour's travel of one of these. Three diagnostic groups (psoriasis, eczema and leg ulcers) accounted for 83% of in-patient days. Patients were admitted principally because of disease severity but many, including half of those with psoriasis, had concurrent medical problems such as alcohol abuse, psychiatric disorder or arthropathy. Many patients with psoriasis and leg ulcers were from socially deprived areas, as defined by low Carstairs index scores, and a similar proportion received income support. Eighteen per cent of patients, mainly those with acute disorders, would have needed admission irrespective of dermatology bed availability. Out-patient management was considered the next best alternative for only 28% of patients, and many patients would have been expected to treat themselves. By contrast, 84% of patients admitted were cleared or substantially improved, or had procedures completed as planned, and another 12% were partially improved. Outcomes were particularly good in psoriasis, eczema and infection groups. We have demonstrated that in-patient management is highly effective in providing remission in chronic skin disease, and our survey also suggests that concomitant disability or social factors mean that for many such patients ambulatory care cannot replace this service.

Dermatology↗
PubMed1999

Epidermolytic palmoplantar keratoderma due to a novel type of keratin mutation, a 3-bp insertion in the keratin 9 helix termination motif.

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by diffuse keratoderma, typically with an erythematous border. Histologically, palmoplantar epidermis shows suprabasal cytolysis and ultrastructurally, tonofilament aggregation with overlying epidermolytic hyperkeratosis. Mutations in the KRT9 gene, encoding keratin 9 (K9), a cytoskeletal protein expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, have been reported to cause EPPK. To date, all KRT9 defects reported in EPPK have been missense mutations in exon 1, which encodes the start of the alpha-helical rod domain. However, based on studies of other keratin disorders, it was postulated that mutations at the other end of the rod domain might also produce the EPPK phenotype. Here, we report the first mutation in the 2B domain of KRT9, 1362ins3, leading to an insertion of histidine in the helix termination motif of the K9 polypeptide. Insertional mutations have not been previously described in keratins. The phenotype of this case is similar to EPPK caused by 1A domain mutations, demonstrating that mutations in either of the helix boundary motif sequences of K9 are detrimental to keratin function and keratinocyte structure.

Adult↗
PubMed1999

Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1.

Pachyonychia congenita (PC) is a group of inherited ectodermal dysplasias, the characteristic phenotype being hypertrophic nail dystrophy. Two main clinical subtypes, PC-1 and PC-2, are inherited as autosomal dominant disorders, but other less well characterized clinical forms also exist. The PC-1 phenotype may be distinguished by the absence of the epidermal cysts found in PC-2, and it has been shown to be caused by mutations in either keratin K16 or its expression partner, the K6a isoform of K6. Mutations in K16 have also been shown to cause a milder related phenotype, focal non-epidermolytic palmoplantar keratoderma. Recently, we have developed a long-range polymerase chain reaction (PCR) strategy which allows specific amplification of the entire functional K16 gene (KRT16A), without amplification of the two K16 pseudogenes (psiKRT16B and psiKRT16C), enabling mutation analysis based on genomic DNA. Here, using this methodology, we describe novel mutations R127P and Q122P in the helix 1A domain of K16 in two families presenting with PC-1. Both mutations were excluded from 50 normal unrelated individuals by restriction enzyme analysis of K16 PCR fragments. In one family, ultrastructural analysis was performed, revealing distinctive tonofilament abnormalities. Specifically, keratin filament bundles were greatly condensed, but did not form the dense amorphous aggregates seen in a number of other keratin disorders. In the second kindred, autosomal dominant cataract was present in some but not all members affected by PC. As the cataract phenotype did not fully cosegregate with the K16 mutation, and given that K16 is not expressed in the lens, these two phenotypes may be coincidental.

Cataract↗
PubMed1999

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↗
PubMed1999

The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing.

Hypotrichosis of Marie Unna (MU) is an autosomal dominant hair-loss disorder with onset in childhood. A genomewide search for the gene was performed in a large Dutch family using 400 fluorescent microsatellite markers. Linkage was detected with marker D8S258, and analysis of this family and a further British kindred with additional markers in the region gave a combined maximum two-point LOD score of 13.42, with D8S560. Informative recombinants placed the MU gene in a 2.4-cM interval between markers D8S258 and D8S298. Recently, recessive mutations in the hr gene were reported in families with congenital atrichia, and this gene was previously mapped close to the MU interval. By radiation-hybrid mapping, we placed the hr gene close to D8S298 but were unable to exclude it from the MU interval. This, with the existence of the semidominant murine hr allele, prompted us to perform mutation analysis for this gene. Full-length sequencing of hr cDNA obtained from an affected individual showed no mutations. Similarly, screening of all exons of the hr gene amplified from the genomic DNA of an affected individual revealed no mutations. Analysis of expressed sequences and positional cloning of the MU locus is underway.

Alopecia↗
PubMed1999

A missense mutation in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families.

The multiplicity of functions served by intercellular gap junctions is reflected by the variety of phenotypes caused by mutations in the connexins of which they are composed. Mutations in the connexin26 (Cx26) gene ( GJB2 ) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3). We now report a Cx26 mutation in three families with mutilating keratoderma and deafness [Vohwinkel's syndrome (VS; MIM 124500), as originally described]. VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses and moderate degrees of deafness. In a large British pedigree, we have mapped the defect to the Cx26 locus. All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function.

Adolescent↗
PubMed1999

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↗
PubMed1998

Keratin 17 mutations cause either steatocystoma multiplex or pachyonychia congenita type 2.

Pachyonychia congenita type 2 (PC-2; Jackson-Lawler syndrome) is an autosomal dominant disorder characterized by hypertrophic nail dystrophy, mild focal keratoderma, multiple pilosebaceous cysts and other features of ectodermal dysplasia. Keratin 17 (K17) is a differentiation-specific keratin expressed in the nail bed, hair follicle, sebaceous gland and other epidermal appendages. Previously, we have demonstrated that PC-2 is caused by mutations in K17 and that similar mutations in this gene can present as steatocystoma multiplex with little or no nail dystrophy. Here, we describe three unrelated kindreds carrying K17 mutations. Two of these families have identical missense mutations (R94C) in the 1A domain of K17. However, while affected members of one kindred have the classical features of PC-2, affected persons in the other family have the steatocystoma multiplex phenotype. In a third family with PC-2, mutation N92S was detected, bringing the total number of distinct mutations reported in K17 thus far to 11. These results demonstrate that K17 mutations commonly underlie both PC-2 and steatocystoma multiplex and that the alternate phenotypes which arise from these genetic lesions in K17 are independent of the specific mutation involved.

Adolescent↗
PubMed1998

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↗
PubMed1998

Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland.

Epidermolytic palmoplantar keratoderma (EPPK, MIM #144200) is an autosomal dominant disorder in which hyperkeratosis confined to the palms and soles is characterized histologically by cytolysis of suprabasal keratinocytes. Mutations in the keratin 9 gene (KRT9), a type 1 keratin expressed exclusively in the suprabasal keratinocytes of palmoplantar epidermis, have previously been demonstrated in this disorder. Here, we have studied four Northern Irish kindreds presenting with EPPK. By direct sequencing of polymerase chain reaction products, heterozygous missense mutations in exon 1 of KRT9 were detected in all the families. These included a novel mutation M156T; as well as M156V in two kindreds; and R162Q in the remaining family. All mutations were confirmed by reverse strand sequencing and restriction enzyme analysis. The point prevalence of EPPK in Northern Ireland was found to be 4.4 per 100,000. To date, all reported EPPK mutations occur in the helix initiation motif at the start of the central coiled-coil rod domain of K9.

Epidermolysis Bullosa↗