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A D Irvine

Publications and source records attributed to A D Irvine.

At least 37 records · Page 2Linked to original sources
PubMed1999

A mutation detection strategy for the human keratin 6A gene and novel missense mutations in two cases of pachyonychia congenita type 1.

Pachyonychia congenita type 1 (PC-1) is an autosomal dominant ectodermal dysplasia characterized by hypertrophic nail dystrophy, focal non-epidermolytic palmoplantar keratoderma and variable features of oral leukokeratosis and follicular keratosis. Previously, we have shown that this disease can be caused by mutations in type I keratin K16 and one mutation has been reported in its type II keratin expression partner, K6a. Mutation analysis for K6a has been hampered by the presence of multiple copies of the K6 gene in the human genome, of which some are expressed and others are pseudogenes. Here, we describe a mutation detection strategy where the entire KRT6A gene, approximately 7 kb, is specifically amplified by long-range PCR. Using this technique, we have detected two novel mutations in the 1A domain of the K6a polypeptide, N171K and F174S. Mutations were confirmed in the affected individuals and were excluded from 50 unaffected unrelated individuals by restriction enzyme analysis of KRT6A PCR products. Additionally, mutation N171K was confirmed by RT-PCR in mRNA derived from lesional palmoplantar epidermis of an affected individual, confirming the specificity of the genomic PCR for the functional K6a gene. This, together with a similar strategy which we have developed for the K16 gene, provide a robust system for mutation detection and prenatal diagnosis for patients with PC-1.

Amino Acid Substitution↗
PubMed1998

Identification of a novel genetic locus for familial cardiac myxomas and Carney complex.

BACKGROUND: Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown. METHODS AND RESULTS: We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex. Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene. CONCLUSIONS: The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation.

Chromosomes, Human, Pair 17↗
PubMed1998

Evidence for a second genetic locus in Carney complex.

Carney complex (MIM no. 160980) is an autosomal dominant condition of lentiginosis, cutaneous and cardiac myxomas and multiple endocrine neoplasia. A locus for Carney complex has recently been mapped to chromosome 2p16. We have studied two Northern Irish families with this disorder. Linkage analysis was performed on the families using five highly informative dinucleotide repeat markers covering this area. Negative logarithm of the odds scores were obtained for all markers at all recombination fractions. We conclude that Carney complex is genetically as well as clinically heterogeneous.

Breast Neoplasms↗
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↗
PubMed1998

A missense mutation in the zinc-finger domain of the human hairless gene underlies congenital atrichia in a family of Irish travellers.

Congenital atrichia is a rare, recessively inherited form of hair loss affecting both males and females and is characterized by a complete absence of hair follicles. Recently, a mutation in the human hairless gene was implicated in the pathogenesis of congenital atrichia. The human hairless gene encodes a putative single zinc-finger transcription-factor protein with restricted expression in brain and skin, which is believed to regulate catagen remodeling in the hair cycle. In this study, we report the identification of a missense mutation in the zinc-finger domain of the hairless gene in a large inbred family of Irish Travellers with congenital atrichia. The mutated arginine residue is conserved among human, mouse, and rat, suggesting that it is of significant importance to the function of the zinc-finger domain.

Alopecia↗
PubMed1997

Microscopic polyangiitis. Delineation of a cutaneous-limited variant associated with antimyeloperoxidase autoantibody.

BACKGROUND: Microscopic polyangiitis is a systemic small vessel vasculitis, which, although primarily associated with necrotizing and crescentic glomerulonephritis and pulmonary capillaritis, often has cutaneous and musculoskeletal features. Microscopic polyangiitis is strongly associated with antineutrophil cytoplasmic autoantibodies, most often demonstrating a perinuclear immunostaining pattern. This pattern usually demonstrates specificity for antimyeloperoxidase autoantibodies. We report a case of microscopic polyangiitis, which, even after several years, has remained predominantly cutaneous. OBSERVATIONS: We describe a patient with a 22-year history of cutaneous purpuric vasculitis. The lesions occur in crops at 4- to 6-week intervals and are associated with constitutional upset and elevated serologic inflammatory indexes. The antimyeloperoxidase titers closely correlate with disease activity in this patient. After close, long-term review and extensive investigations, no evidence of necrotizing and crescentic glomerulonephritis, pulmonary capillaritis, or other deep-organ involvement has been detected. CONCLUSIONS: To our knowledge, this is the first report of a long-term evaluation of predominantly cutaneous microscopic polyangiitis and demonstrates that serologically characteristic microscopic polyangiitis may remain limited without subsequent progression to characteristic systemic involvement. This observation contributes to the understanding and characterization of the clinicopathologic spectrum of microscopic polyangiitis.

Adult↗
PubMed1997

Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy.

The intermediate filament cytoskeleton of corneal epithelial cells is composed of cornea-specific keratins K3 and K12 (refs 1,2). Meesmann's corneal dystrophy (MCD) is an autosomal dominant disorder causing fragility of the anterior corneal epithelium, where K3 and K12 are specifically expressed. We postulated that dominant-negative mutations in these keratins might be the cause of MCD. K3 was mapped to the type-II keratin gene cluster on 12q; and K12 to the type-I keratin cluster on 17q using radiation hybrids. We obtained linkage to the K12 locus in Meesmann's original German kindred (Zmax = 7.53; theta = 0) and we also showed that the phenotype segregated with either the K12 or the K3 locus in two Northern Irish pedigrees. Heterozygous missense mutations in K3 (E509K) and in K12 (V143L; R135T) completely co-segregated with MCD in the families and were not found in 100 normal unrelated chromosomes. All mutations occur in the highly conserved keratin helix boundary motifs, where dominant mutations in other keratins have been found to severely compromise cytoskeletal function, leading to keratinocyte fragility phenotypes. Our results demonstrate for the first time the molecular basis of Meesmann's corneal dystrophy.

Cornea↗
PubMed1997

A mutation in the V1 domain of keratin 5 causes epidermolysis bullosa simplex with mottled pigmentation.

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP; MIM no 131960) is an autosomal dominant disorder characterized by skin blistering at acral sites, punctate palmo-plantar hyperkeratoses, and mottled pigmentation of the trunk and proximal extremities. Histologically and ultrastructurally, the blistering in EBS-MP closely resembles that found in other EBS subtypes. This is consistent with a disorder of the basal keratinocyte cytoskeleton, in which several groups have found disease-causing mutations within the central rod domains of keratins 5 and 14. We have identified a C --> T transition at base position 71 of K5 causing a P24L substitution in a sporadic case of EBS-MP. Recently, this same mutation was identified in two unrelated families with EBS-MP.

Epidermolysis Bullosa Simplex↗
PubMed1997

A novel mutation in the helix termination peptide of keratin 5 causing epidermolysis bullosa simplex Dowling-Meara.

Epidermolysis bullosa simplex Dowling-Meara (MIM# 1317600) is the most severe of the three common epidermolysis bullosa simplex subtypes. In addition to the palmoplantar distribution seen in other epidermolysis bullosa simplex subtypes, extensive herpetiform blistering spontaneously develops on the trunk and limbs and may lead to scarring or milia formation. The keratin 5 and keratin 14 genes encode proteins that form the primary structural components of the basal epidermal keratinocytes, mutations in either of these genes can cause epidermolysis bullosa simplex. In this study we sequenced these genes in a family with epidermolysis bullosa simplex Dowling-Meara. We report a novel T to C transition in the helix termination peptide of K5 that causes a nonconservative substitution of a highly conserved amino acid within this critical region (I466T). This mutation adds to those previously reported and provides further evidence of phenotype-genotype correlation in epidermolysis bullosa simplex.

Amino Acid Sequence↗
PubMed1997

Carney complex: report of a kindred with predominantly cutaneous manifestations.

We report a four-generation kindred with the complex of myxomas, spotty pigmentation and endocrine overactivity. This kindred demonstrates a relatively limited phenotypic expression with predominance of cutaneous features. Male-to-male transmission confirms the autosomal dominant nature of the condition. We propose that pilonidal sinus may be an associated manifestation in this kindred.

Adult↗
PubMed1996

An autosomal dominant syndrome of acromegaloid facial appearance and generalised hypertrichosis terminalis.

We report a family in which a phenotype of acromegaloid facial appearance (AFA) and generalised hypertrichosis terminalis segregates through three generations. Congenital hypertrichosis terminalis and AFA have been previously reported as independent autosomal dominant traits. This is the first report to delineate an autosomal dominant transmission of the combined phenotype.

Acromegaly↗
PubMed1996

Dermatological presentation of disease associated with antineutrophil cytoplasmic antibodies: a report of two contrasting cases and a review of the literature.

Antineutrophil cytoplasmic antibody (ANCA)-associated disease (AAD) constitutes a pathological disease spectrum of a necrotizing vasculitis of small- and medium-sized vessels, extravascular granuloma formation, and necrotizing and crescentic glomerulonephritis, and also a clinical disease continuum which ranges from renal-limited disease to a widespread systemic vasculitis, including Wegener's granulomatosis and microscopic polyangiitis. In the latter, circulating ANCA are an aid to diagnosis and also may play a pathogenic part. Two contrasting patients with AAD are described, both of whom presented primary with dermatological features. These included a cutaneous purpuric vasculitis, orogenital ulceration, infarction of the fingertip, and pyoderma gangrenosum-like ulceration. These cases will familiarize dermatologists with both the concept and dermatological features of AAD.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1996

Lymphangioma circumscriptum associated with paravesical cystic retroperitoneal lymphangioma.

A boy with long-standing congenital cutaneous lymphangioma circumscriptum (LC), presented at the age of 6 years with an episode of painless haematuria, subsequently attributed to bladder wall involvement of a paravesical cystic retroperitoneal lymphangioma. Magnetic resonance imaging demonstrated this lymphangioma to be in communication with the cutaneous lesions. Deep lymphatic and visceral involvement is an extremely unusual occurrence in association with LC. This is the first report of an association between LC and cystic retroperitoneal lymphangioma. LC occasionally heralds a deeper, more clinically significant lymphangioma which may not become apparent until many years after the initial dermatological presentation. We report this case to raise awareness of this potential association and to demonstrate the usefulness of magnetic resonance imaging in the assessment of the deep component of cutaneous lymphangiomas.

Child↗