Exclusion of PTEN, CTNNB1, and PTCH as candidate genes for Birt-Hogg-Dube syndrome.
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Adult↗
Biomedical subjects
S J Bale
Publications and source records attributed to S J Bale.
The morbid anatomy of the dermatologic genome: an update for the third millennium.
BACKGROUND: Much progress has been made in recent years in the identification of genes underlying many hereditary skin diseases. OBJECTIVE: To provide an update on the status of the identification of genes involved in hereditary skin disorders and to compare the current standing with that in the last decade. METHODS: A review of the literature is presented here in a series of lists describing the chromosomal location, specific gene, clinical relevance, and availability of molecular-based genetic tests for each genodermatosis. RESULTS: Progress has been made in identifying the genes underlying many disorders of cornification, genodermatoses with malignant potential, bullous disorders, pigmentary disorders, disorders affecting the epidermal appendages and the dermis, and other miscellaneous genodermatoses. CONCLUSION: The great progress made toward the completion of the human gene sequence and the continued efforts of many clinical and molecular scientists to identify disease genes will make diagnosis of hereditary dermatological disorders more precise and allow accurate family counseling as well as possibly leading to more targeted therapies during this millennium.
Cell Transformation, Neoplastic↗
Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation.
Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.
Calcium-Transporting ATPases↗
Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico.
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and a storage pool deficiency due to an absence of platelet dense bodies. Lysosomal ceroid lipofuscinosis, pulmonary fibrosis and granulomatous colitis are occasional manifestations of the disease. HPS occurs with a frequency of one in 1800 in north-west Puerto Rico due to a founder effect. Several non-Puerto Rican patients also have mutations in HPS1, which produces a protein of unknown function. Another gene, ADTB3A, causes HPS in the pearl mouse and in two brothers with HPS-2 (refs. 11,12). ADTB3A encodes a coat protein involved in vesicle formation, implicating HPS as a disorder of membrane trafficking. We sought to identify other HPS-causing genes. Using homozygosity mapping on pooled DNA of 6 families from central Puerto Rico, we localized a new HPS susceptibility gene to a 1.6-cM interval on chromosome 3q24. The gene, HPS3, has 17 exons, and a putative 113.7-kD product expected to reveal how new vesicles form in specialized cells. The homozygous, disease-causing mutation is a large deletion and represents the second example of a founder mutation causing HPS on the small island of Puerto Rico. We also present an allele-specific assay for diagnosing individuals heterozygous or homozygous for this mutation.
Alleles↗
The spectrum of pathogenic mutations in SPINK5 in 19 families with Netherton syndrome: implications for mutation detection and first case of prenatal diagnosis.
The Comèl-Netherton syndrome is an autosomal recessive multisystemic disorder characterized by localized or generalized congenital ichthyosis, hair shaft abnormalities, immune deficiency, and markedly elevated IgE levels. Life-threatening complications during infancy include temperature and electrolyte imbalance, recurrent infections, and failure to thrive. To study the clinical presentations of the Comèl-Netherton syndrome and its molecular cause, we ascertained 19 unrelated families of various ethnic backgrounds. Results of initial linkage studies mapped the Comèl-Netherton syndrome in 12 multiplex families to a 12 cM interval on 5q32, thus confirming genetic homogeneity of Comèl-Netherton syndrome across families of different origins. The Comèl-Netherton syndrome region harbors the SPINK5 gene, which encodes a multidomain serine protease inhibitor (LEKTI) predominantly expressed in epithelial and lymphoid tissues. Recently, recessive mutations in SPINK5 were identified in several Comèl-Netherton syndrome patients from consanguineous families. We used heteroduplex analysis followed by direct DNA sequencing to screen all 33 exons and flanking intronic sequences of SPINK5 in the affected individuals of our cohort. Mutation analysis revealed 17 distinct mutations, 15 of which were novel, segregating in 14 Comèl-Netherton syndrome families. The nucleotide changes included four non-sense mutations, eight small deletions or insertions leading to frameshift, and five splice site defects, all of which are expected to result in premature terminated or altered translation of SPINK5. Almost half of the mutations clustered between exons 2 and 8, including two recurrent mutations. Genotype-phenotype correlations suggested that homozygous nucleotide changes resulting in early truncation of LEKT1 are associated with a severe phenotype. For the first time, we used molecular data to perform prenatal testing, thus demonstrating the feasibility of molecular diagnosis in the Comèl-Netherton syndrome.
Adolescent↗
Splice-site mutation in TGM1 in congenital recessive ichthyosis in American families: molecular, genetic, genealogic, and clinical studies.
Lamellar ichthyosis (LI, OMIM no. 242300) is a severe autosomal recessive genodermatosis with an estimated prevalence of 1:200,000. LI represents one end of the spectrum of congenital recessive ichthyosis (CRI). Mutations in the gene for transglutaminase-1 (TGM1) are responsible for many cases of LI and occur throughout the coding sequence of the gene. Our analyses of patients with CRI revealed a common TGM1 mutation involving loss of the intron 5 splice acceptor site leading to alternative splicing of the message. We found families in which the splice acceptor site mutation was homozygous, and families where the patients were compound heterozygotes for the splice acceptor site mutation and another TGM1 mutation. A mutation at this same site occurs in the majority of Norwegian patients as a founder effect. In our ethnically diverse patient population, none of whom have known Norwegian ancestry, haplotype analysis of the TGM1 chromosomal region also suggested the existence of a founder effect. Comparison of the common haplotype in our data with the Norwegian data showed that 2/7 of our splice acceptor site mutation chromosomes had the full reported Norwegian haplotype, and the remaining five chromosomes exhibited recombination at the most distal marker studied. History, family origins, and haplotype analysis suggested that the mutation originally arose on a German background and was introduced into Norway around 800-1000 AD. We also found a limited correlation between genotype and phenotype in our study, with the four homozygous patients having less severe disease than many of the heterozygotes, and no patient with a splice acceptor site mutation having erythroderma or a congenital ichthyosiform erythroderma phenotype.
Adolescent↗
The spectrum of mutations in erythrokeratodermias--novel and de novo mutations in GJB3.
Intercellular channels in skin are a complex and functionally diverse system formed by at least eight connexins (Cx). Our recent molecular studies implicating Cx defects in inherited skin disorders emphasize the critical role of this signaling pathway in epidermal differentiation. Erythrokeratodermia variabilis (EKV) is an autosomal dominant genodermatosis with a striking phenotype characterized by the independent occurrence of transient localized erythema and hyperkeratosis. The disease maps to 1p34-p35, and recently we identified the causative gene GJB3 encoding Cx31. We have now investigated GJB3 in two families and three sporadic cases with EKV, and report three new heterozygous mutations. In a sporadic case, we detected a mutation leading to substitution of a conserved phenylalanine (F137L) in the third transmembrane domain, which likely interferes with the proper assembly or gating properties of connexons. In another family, all three affected individuals carried two distinct mutations on the same GJB3 allele. However, only a de novo heterozygous missense mutation replacing arginine 42 with proline (R42P) co-segregated with the disease, while a 12 bp deletion predicted to eliminate four amino acid residues in the variable carboxy terminal domain of Cx31 was also found in clinically unaffected relatives but not in 90 unaffected controls. Including the previously published mutations, in toto, five different missense mutations have now been detected in 6 out of 17 families investigated by our laboratory, all of which presumably affect the cytoplasmic amino terminal and transmembrane domains of Cx31. In contrast, two mutations linked to progressive high-tone hearing impairment were located in the second extracellular domain, suggesting that the character and position of Cx mutations determine their phenotypic expression in different tissues. However, the phenotypic spectrum of GJB3 mutations seems not to include progressive symmetric erythrokeratodermia, another dominant genodermatosis with overlapping features, since no mutations were found in six unrelated families tested.
Connexins↗
Netherton syndrome is not linked to 18q12, a region homologous to the murine lanceolate hair (lah) locus.
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Animals↗
A new xeroderma pigmentosum group C poly(AT) insertion/deletion polymorphism.
We found a common biallelic polymorphism (PAT) in the xeroderma pigmentosum complementation group C (XPC) DNA repair gene consisting of an insertion of 83 bases of A and T [poly(AT)] and a 5 base deletion within intron 9. We developed a PCR assay to resolve the XPC PAT+ and PAT- alleles and found that the PAT+ allele frequency was 0.44 in 156 cancer-free donors from the Johns Hopkins School of Public Health, 0.41 in 263 cancer-free donors from the Baltimore Longitudinal Study of Aging and 0.36 in samples from 216 unselected donors from NIH. We also found a single nucleotide polymorphism in exon 15 of the XPC gene (A2920C, Lys939-->Gln) that creates a new enzyme restriction site. This XPC exon 15 single nucleotide polymorphism occurred at a frequency of 0.38 in 98 NIH donors and is in linkage disequilibrium with the PAT locus. We developed an allele-specific complementation assay utilizing post-UV host cell reactivation to assess DNA repair capacity of polymorphic alleles. We found similar DNA repair with XPC 2920A and XPC 2920C. These common polymorphisms in the XPC DNA repair gene may be useful for molecular epidemiological studies of cancer susceptibility.
Adolescent↗
Genetic basis of Darier-White disease: bad pumps cause bumps.
BACKGROUND: Darier-White disease, or keratosis follicularis, is a dominantly inherited disorder characterized by brown hyperkeratotic papules and plaques in a seborrheic distribution. The genetic basis of this disorder has recently been elucidated. OBJECTIVE: In this article, we review the history of the search for the genetic basis of Darier-White disease. METHODS: Previous studies are reviewed in which linkage studies identified the chromosomal location of the disease gene. The methods of physical mapping of the critical gene region and the screening of candidate genes are discussed. Results of recently published data on genotype-phenotype correlation in the disorder are presented. RESULTS: Linkage analysis in families, together with development of a physical map of the critical region was important in identifying the causative gene. Screening of candidate genes led to the discovery that mutations in ATP2A2, a gene that encodes the sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2, cause Darier-White disease. Abnormalities in the function of this calcium pump are hypothesized to interfere with cell growth and differentiation calcium-dependent processes. CONCLUSION: Genetic and molecular approaches have identified the gene for Darier-White disease and lead to more questions, including "Will this information help in the search for the Hailey-Hailey disease gene?"
Chromosome Mapping↗
Mutation screening using automated bidirectional dideoxy fingerprinting.
The need continues to grow for mutation identification in genetic disease in both research and clinical settings. We have developed a rapid nonradioactive bidirectional dideoxy fingerprint mutation screening procedure that is performed using an automated DNA analyzer. This technique features standardized primers and easily interpreted results from separate, but simultaneously collected, images for coding and noncoding strands. Another advantage is simplified mutation verification by sequencing using the same amplified DNA templates and also application to large multi-exon genes. We demonstrate the efficiency and reproducibility of the method in which we screen a DNA fragment encompassing exon 5 of the PTCH gene (in which mutations cause Gorlin Syndrome) in a panel of 22 patients.
Basal Cell Nevus Syndrome↗
Recent advances in gene mapping of skin diseases. Pseudoxanthoma elasticum: A satisfying sibling study.
BACKGROUND: A review of the recent progress made in mapping of the hereditary skin disease pseudoxanthoma elasticum is presented. METHODS: Affected sib pair methods, parametric linkage analysis, and linkage heterogeneity tests are reviewed as applied to the effort to identify the location of the pseudoxanthoma elasticum gene. RESULTS: Families segregating either autosomal dominant or autosomal recessive pseudoxanthoma elasticum mapped to chromosome 16p13.1. CONCLUSION: There is a gene for pseudoxanthoma elasticum on chromosome 16p. The underlying molecular defect remains to be elucidated.
Chromosome Mapping↗
The "sins" of the fathers: self-healing squamous epithelioma in Scotland.
BACKGROUND: A review is presented of the recent progress made in mapping of the hereditary skin disease "Ferguson-Smith multiple self-healing squamous epithelioma." METHODS: The use of founder effects in an autosomal dominant disease is reviewed as applied to gene mapping efforts. RESULTS: A common haplotype among Scottish families segregating Ferguson-Smith disease allowed the narrowing of the candidate gene interval and the identification of several possible disease-associated genes. CONCLUSION: The gene for Ferguson-Smith multiple self-healing squamous epithelioma lies in a narrow region on chromosome 9q, along with several other important hereditary skin disease loci.
Basal Cell Nevus Syndrome↗
Of hairless mice and men: the genetic basis of congenital alopecia universalis/congenital atrichia.
BACKGROUND: Mouse models of human diseases help identify gene defects. OBJECTIVE: The methods of homozygosity mapping and mouse/human homology to identify genes are reviewed. The genotype/phenotype correlation in two clinical entities with mutations in the human hairless gene are discussed. METHODS: The example of the hairless mouse's contribution to our knowledge of hereditary alopecia is used, and the utility of consanguineous families for genetic studies is highlighted. RESULTS: Mutations in the human homolog of the mouse hairless gene lead to congenital alopecia universalis and atrichia with papules. CONCLUSION: A mouse model of congenital alopecia has led to understanding the molecular basis of at least one type of severe human alopecia.
Alopecia↗
Familial autoimmunity in pedigrees of idiopathic inflammatory myopathy patients suggests common genetic risk factors for many autoimmune diseases.
OBJECTIVE: To test the hypothesis that many autoimmune diseases share common genetic risk factors and to define the frequency and distribution of autoimmune diseases in relatives of patients with very rare disorders, the idiopathic inflammatory myopathies (IIM). METHODS: We evaluated, in a prospective case-control study, consecutive patients with IIM who were referred to our center and ascertained without regard to family history or known risk factors for autoimmunity, and all available family members. We used a standardized assessment to determine the presence and type of autoimmune disease in each subject. A matched comparison group of control subjects without autoimmune disease who were referred to our center and their families were similarly assessed. RESULTS: Autoimmune diseases were significantly increased in prevalence (21.9%) in the 151 first-degree relatives of the 21 IIM probands compared with the prevalence (4.9%) in the 143 relatives of the 21 control probands (odds ratio [OR] by regression analysis 7.9, 95% confidence interval [95% CI] 2.9-21.9, P < 0.001). Women had more autoimmune disease than men (OR by regression analysis 4.6, 95% CI 2.3-9.0) and the odds ratio for autoimmune disease increased 0.02 per year of age. These disorders tended to follow the frequency distribution of autoimmune diseases in the general population. Genetic modeling studies showed that a non-Mendelian polygenic inheritance pattern for autoimmune disease was most consistent with these data. CONCLUSION: Autoimmune diseases are significantly increased in frequency in first-degree relatives of IIM patients, affect more women than men, increase with age, and are distributed in a pattern similar to that in the general population. Many autoimmune disorders share genes that together act as polygenic risk factors for autoimmunity.
Adolescent↗
Rheumatoid arthritis in the Pima Indians: the intersection of epidemiologic, demographic, and genealogic data.
OBJECTIVE: To describe the clinical features and familial distribution of rheumatoid arthritis (RA) in the Pima Indians. METHODS: From 1965 through 1990, all cases of RA as defined by the American College of Rheumatology (formerly, the American Rheumatism Association) 1987 criteria or all cases of seropositive, erosive disease as defined by the Rome criteria were identified in individuals who were age 20 years and older and were of 50% or more Pima/Tohono-O'odham heritage. Radiographs were reviewed by 2 musculoskeletal radiologists who were blinded to case status. Kinship coefficients were used to evaluate familial aggregation. RESULTS: Eighty-eight RA cases were identified from this population-based sample. Over 66% of the cases had seropositive disease, over 60% had erosive disease, and over 40% had subcutaneous nodules. Of the 88 RA cases, 40 were members of families with more than 1 RA case. The remainder were simplex cases. CONCLUSION: In this population, clinical markers of severe RA were present in a majority of cases. The presence of familial aggregation for RA in the Pima Indians suggests underlying genetic factors in disease pathogenesis.
Adult↗
Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma.
Mutations in GJB2 encoding the gap junction protein connexin-26 (Cx26) have been established as the basis of autosomal recessive non-syndromic hearing loss. The involvement of GJB2 in autosomal dominant deafness has also been proposed, although the putative mutation identified in one family with both deafness and palmoplantar keratoderma has recently been suggested to be merely a non-disease associated polymorphism. We have observed a similar phenotype in an Egyptian family that segregated with a heterozygous missense mutation of GJB2, leading to a non-conservative amino acid substitution (R75W). The deleterious dominant-negative effect of R75W on gap channel function was subsequently demonstrated in the paired oocyte expression system. Not only was R75W alone incapable of inducing electrical conductance between adjacent cells, but it almost completely suppressed the activity of co-expressed wildtype protein. The Cx26 mutant W77R, which has been implicated in autosomal recessive deafness, also failed to form functional gap channels by itself but did not significantly interfere with the function of wildtype Cx26. These data provide compelling evidence for the serious functional consequences of Cx26 mutations in dominant and recessive deafness.
Amino Acid Sequence↗
Familial clustering of rheumatoid arthritis with other autoimmune diseases.
Previous studies have shown that rheumatoid arthritis aggregates within families. However, no formal genetic analysis of rheumatoid arthritis in pedigrees together with other autoimmune diseases has been reported. We hypothesized that there are genetic factors in common in rheumatoid arthritis and other autoimmune diseases. Results of odds-ratio regression and complex segregation analysis in a sample of 43 Caucasian pedigrees ascertained through a rheumatoid arthritis proband or matched control proband, revealed a very strong genetic influence on the occurrence of both rheumatoid arthritis and other autoimmune diseases. In an analysis of rheumatoid arthritis alone, only one inter-class measure, parent-sibling, resulted in positive evidence of aggregation. However, three inter-class measures (parent-sibling, sibling-offspring, and parent-offspring pairs) showed significant evidence of familial aggregation with odds-ratio regression analysis of rheumatoid arthritis together with all other autoimmune diseases. Segregation analysis of rheumatoid arthritis alone revealed that the mixed model, including both polygenic and major gene components, was the most parsimonious. Similarly, segregation analysis of rheumatoid arthritis together with other autoimmune diseases revealed that a mixed model fitted the data significantly better than either major gene or polygenic models. These results were consistent with a previous study which concluded that several genes, including one with a major effect, is responsible for rheumatoid arthritis in families. Our data showed that this conclusion also held when the phenotype was defined as rheumatoid arthritis and/or other autoimmune diseases, suggesting that several major autoimmune diseases result from pleiotropic effects of a single major gene on a polygenic background.
Adult↗