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Biomedical subjects

S M Leal

Publications and source records attributed to S M Leal.

At least 19 recordsLinked to original sources
PubMed2006

Ectodermal dysplasia of hair and nail type: mapping of a novel locus to chromosome 17p12-q21.2.

BACKGROUND: Ectodermal dysplasias (EDs) describe a large and complex group of disorders characterized by abnormal development of the skin and appendages (hair, nails, teeth and sweat glands). Of the approximately 200 different EDs, about 30 have been studied at the molecular level. In an effort to understand the molecular bases of ED of hair and nail type, we studied a Pakistani consanguineous family with multiple affected individuals. OBJECTIVES: To localize the gene responsible for the autosomal recessive form of ED of hair and nail type. METHODS: Genotyping of nine members of the family, including five affected and four normal individuals was performed using microsatellite markers mapping to candidate regions, harbouring genes involved in related phenotypes. Five epithelial keratin genes located in the candidate region were sequenced to identify the pathogenic mutation. RESULTS: We mapped the disease locus to a 24.2-cM interval flanked by markers D17S839 and D17S1299 on chromosome 17p12-q21.2 (Z(max) = 4.4). DNA sequencing of five epithelial keratin candidate genes, present in the disease locus, did not reveal any pathogenic mutation in the affected individuals. CONCLUSIONS: The gene for ED of hair and nail type has been mapped to chromosome 17p12-q21.2 in a Pakistani consanguineous family. Failure to detect mutations in epithelial keratin genes suggests that the mutation may lie either in regulatory regions of one of the epithelial keratin genes or in another unknown gene, located in the linkage interval, with a possible role in the development of ectodermal appendages.

Chromosome Mapping↗
PubMed2006

A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31.

Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five-generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2-q26.31 by carrying out a genome scan followed by fine mapping. A maximum two-point logarithm of odds (LOD) score of 2.93 at theta=0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6-cM region according to the Rutgers combined linkage-physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2.

Alopecia↗
PubMed2006

A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type.

BACKGROUND: Ectodermal dysplasias are developmental disorders affecting tissues of ectodermal origin. To date, four different types of ectodermal dysplasia involving only hair and nails have been described. In an effort to understand the molecular bases of this form of ectodermal dysplasia, large Pakistani consanguineous kindred with multiple affected individuals has been ascertained from a remote region in Pakistan. OBJECTIVE: To identify the gene underlying the phenotype. METHODS: Microsatellite markers were genotyped in candidate regions and two point and multipoint parametric linkage analysis carried out. RESULTS: The disease locus was mapped to a 16.6 centimorgan region on chromosome 12q12-q14.1 (Zmax = 8.2), which harbours six type II hair keratin genes. DNA sequence analysis revealed a homozygous missense mutation in the hair matrix and cuticle keratin KRTHB5, leading to histidine substitution of a conserved arginine residue (R78H) located in the head domain. CONCLUSIONS: This report provides the first direct evidence relating to the molecular pathogenesis of pure hair-nail ectodermal dysplasias.

Arginine↗
PubMed2006

AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3.

BACKGROUND: We report here the genetic characterisation of a large five generation Chinese family with the phenotypic features of auditory neuropathy and progressive peripheral sensory neuropathy, and the genetic feature of X linked recessive inheritance. Disease onset was at adolescence (at an average age of 13 years for six affected subjects). The degree of hearing impairment varied from mild to severe, with decreased otoacoustic emissions; auditory brainstem responses were lacking from onset. METHODS: Two-point and multipoint model based linkage analysis using the MILNK and LINKMAP programs of the FASTLINK software package produced maximum two-point and multipoint LOD scores of 2.41 and 2.41, respectively. RESULTS: These findings define a novel X linked auditory neuropathy locus/region (AUNX1, Xq23-q27.3). This region is 42.09 cM long and contains a 28.07 Mb region with flanking markers DXS1220 and DXS8084, according to the Rutgers Combined Linkage-Physical Map, build 35. However, mutation screen of the candidate gene SLC6A14 within the region did not identify the causative genetic determinant for this large Chinese family.

China↗
PubMed2005

Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.

The Pakistani population has become an important resource for research on autosomal recessive non-syndromic hearing impairment (ARNSHI) due to the availability of large extended and highly consanguineous pedigrees. Here is presented the first report on the prevalence of gap junction beta-2 (GJB2) variants in Pakistan. One hundred and ninety-six unrelated Pakistani families with ARNSHI were recruited for a study on the genetics of NSHI. DNA sequencing of the GJB2 coding region was done on two affected individuals per family. Evolutionary conservation and predicted effect on the protein product were studied in order to hypothesize whether or not a variant was potentially deleterious. Homozygous putatively functional GJB2 variants were identified in 6.1% of families. None of the putatively functional GJB2 variants were observed in the compound heterozygous state. The six putatively causative variants noted were 231G > A(W77X), 71G > A(W24X), 167delT, 95G > A(R32H), 358-360delGAG(delE120), and 269T > C(L90P), with 231G > A(W77X) and 71G > A(W24X) being the most common. In addition, five benign polymorphisms, 380G > A(R127H), 457G > A(V153I), 493C > T(R165W), 79G > A(V27I), and 341 A > G(E114G), were identified within this population. In a few individuals, benign polymorphisms were observed to occur on the same haplotype, namely [457G > A(V153I); 493C > T(R165W)] and [79G > A(V27I); 341 A > G(E114G)]. The spectrum of GJB2 sequence variants in Pakistan may reflect shared origins of hearing impairment alleles within the Indian subcontinent. The high degree of consanguinity within Pakistan may have maintained the GJB2 prevalence at a much lower rate than within India and other populations.

Connexin 26↗
PubMed2005

Localization of a novel autosomal recessive non-syndromic hearing impairment locus DFNB55 to chromosome 4q12-q13.2.

Hereditary hearing impairment (HI) is the most genetically heterogeneous trait known in humans. So far, 54 autosomal recessive non-syndromic hearing impairment (ARNSHI) loci have been mapped, and 21 ARNSHI genes have been identified. Here is reported the mapping of a novel ARNSHI locus, DFNB55, to chromosome 4q12-q13.2 in a consanguineous Pakistani family. A maximum multipoint LOD score of 3.5 was obtained at marker D4S2638. The region of homozygosity and the 3-unit support interval are flanked by markers D4S2978 and D4S2367. The region spans 8.2 cm on the Rutgers combined linkage-physical map and contains 11.5 Mb. DFNB55 represents the third ARNSHI locus mapped to chromosome 4.

Chromosome Mapping↗
PubMed2005

Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome).

BACKGROUND: Majeed syndrome is an autosomal recessive, autoinflammatory disorder characterised by chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. The objectives of this study were to map, identify, and characterise the Majeed syndrome causal gene and to speculate on its function and role in skin and bone inflammation. METHODS: Six individuals with Majeed syndrome from two unrelated families were identified for this study. Homozygosity mapping and parametric linkage analysis were employed for the localisation of the gene responsible for Majeed syndrome. Direct sequencing was utilised for the identification of mutations within the genes contained in the region of linkage. Expression studies and in silico characterisation of the identified causal gene and its protein were carried out. RESULTS: The phenotype of Majeed syndrome includes inflammation of the bone and skin, recurrent fevers, and dyserythropoietic anaemia. The clinical picture of the six affected individuals is briefly reviewed. The gene was mapped to a 5.5 cM interval (1.8 Mb) on chromosome 18p. Examination of genes in this interval led to the identification of homozygous mutations in LPIN2 in affected individuals from the two families. LPIN2 was found to be expressed in almost all tissues. The function of LPIN2 and its role in inflammation remains unknown. CONCLUSIONS: We conclude that homozygous mutations in LPIN2 result in Majeed syndrome. Understanding the aberrant immune response in this condition will shed light on the aetiology of other inflammatory disorders of multifactorial aetiology including isolated chronic recurrent multifocal osteomyelitis, Sweet syndrome, and psoriasis.

Adult↗
PubMed2004

Localization of a novel locus for hereditary nail dysplasia to chromosome 17q25.1-17q25.3.

We report on a six-generation Pakistani consanguineous family with autosomal recessive transmission of a form of hereditary nail dysplasia. Affected individuals presented with onycholysis of fingernails and anonychia of toenails. Associated abnormalities of ectodermal appendages were not observed in any of the affected individuals. Linkage has been established to chromosome 17q. A maximum multipoint analysis logarithm of the odds ratio score of 4.85 was obtained at marker D17S1301. Due to the consanguineous nature of this kindred, the gene for nail dysplasia is probably contained within a 5.0-cM (3 MB on the sequence-based physical map) region of homozygosity flanked by markers D17S1807 and D17S937.

Chromosomes, Human, Pair 17↗
PubMed2003

Mutations in the gamma-actin gene (ACTG1) are associated with dominant progressive deafness (DFNA20/26).

Age-related hearing loss (presbycusis) is a significant problem in the population. The genetic contribution to age-related hearing loss is estimated to be 40%-50%. Gene mutations that cause nonsyndromic progressive hearing loss with early onset may provide insight into the etiology of presbycusis. We have identified four families segregating an autosomal dominant, progressive, sensorineural hearing loss phenotype that has been linked to chromosome 17q25.3. The critical interval containing the causative gene was narrowed to approximately 2 million bp between markers D17S914 and D17S668. Cochlear-expressed genes were sequenced in affected family members. Sequence analysis of the gamma-actin gene (ACTG1) revealed missense mutations in highly conserved actin domains in all four families. These mutations change amino acids that are conserved in all actins, from protozoa to mammals, and were not found in >100 chromosomes from normal hearing individuals. Much of the specialized ultrastructural organization of the cells in the cochlea is based on the actin cytoskeleton. Many of the mutations known to cause either syndromic or nonsyndromic deafness occur in genes that interact with actin (e.g., the myosins, espin, and harmonin). The mutations we have identified are in various binding domains of actin and are predicted to mildly interfere with bundling, gelation, polymerization, or myosin movement and may cause hearing loss by hindering the repair or stability of cochlear cell structures damaged by noise or aging. This is the first description of a mutation in cytoskeletal, or nonmuscle, actin.

Actins↗
PubMed2003

A second kindred linked to DFNA20 (17q25.3) reduces the genetic interval.

A family ascertained in the United States displays significant evidence of linkage to 17q25.3 (maximum two-point LOD score 6.32). The non-syndromic autosomal-dominant hearing-loss loci DFNA20 and DFNA26 map to this region. The 3-unit support interval and haplotype for this USA kindred falls within the interval for DFNA20 and DFNA26 and reduces the region to 6.05 cM, according to the deCode genetic map. The same gene is probably responsible for both DFNA20/DFNA26. In addition, the USH1G locus maps to this region and could be an allelic variant of the gene responsible for DFNA20/DFNA26. Clinical data is presented for this kindred, where hearing-impaired family members present with sloping audiograms with mid- and high-frequency hearing loss, which progresses to hearing loss that affects all frequencies. The mean age of onset of hearing impairment is 13.2 years of age (standard deviation: 4.6 years).

Adult↗
PubMed2001

Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss.

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.

Alleles↗
PubMed2001

Novel and previously reported single-nucleotide polymorphisms in the human 5-HT(1B) receptor gene: no association with cocaine or alcohol abuse or dependence.

Evidence from animal self-administration and human genetics studies suggests that the serotonin(1B) (5-HT(1B)) receptor may be involved in modulating responses to cocaine or alcohol. We hypothesize that polymorphisms, including single-nucleotide polymorphisms (SNPs), in the human 5-HT(1B) receptor gene, may be associated with individual differences in vulnerability to cocaine or alcohol abuse or dependence. A total of 210 subjects were studied, including individuals with a primary diagnosis (DSM-IV criteria) of cocaine abuse or dependence, alcohol abuse or dependence, and controls with no history of previous or current illicit drug or alcohol abuse or dependence. Genomic DNA samples were isolated from each individual. For 157 of the subjects, polymerase chain reaction (PCR) was used to amplify the entire coding region of the 5-HT(1B) receptor gene as well as parts of the 5' and 3' untranslated regions. PCR products were sequenced in forward and reverse directions on an automated sequencer. Amplified DNA from an additional 53 subjects was sequenced in the 5' untranslated region to gain additional data on the frequency of one identified SNP. Seven polymorphisms were identified: one novel SNP in the 5' untranslated region (UTR) of the gene (A-161T); one SNP not reported in any published scientific communication (but found to be recorded in GenBank) in the 3' UTR (A1180G); two novel dinucleotide deletions at positions - 184/- 183 and - 182/- 181; and three previously identified SNPs (T-261G, C129T, G861C). Data were stratified by ethnicity and pooled Relative Risk was calculated for combined alcohol abuse and dependence cases and controls, and also for combined cocaine abuse and dependence cases and controls. No significant differences between cases and controls were found.

Alcoholism↗
PubMed2001

Phenotypes and genetic analysis of psychiatric and neuropsychiatric traits.

A workshop was held at Rockefeller University entitled "Phenotypes and Genetic Analysis of Complex Traits." The purpose of the workshop was to examine phenotype definition for complex traits, in particular, psychiatric and neuropsychiatric traits. An additional goal of the workshop was to examine statistical genetic approaches that specifically address the oligogenic nature of psychiatric traits. An overview of topics that were addressed and discussed at the workshop is presented in this article.

Animals↗
PubMed2001

Novel selection criteria for genome scans of complex traits.

Due to their oligogenic inheritance, the identification of susceptibility loci for complex traits by classical selection criteria has not been very successful. One way to address this problem is to identify statistics that measure the effect of more than one locus simultaneously. In the approach described here, a p-value is assigned to a combination of loci under the null hypothesis that none of them is linked to the disease locus. In order to examine the power of this method to detect multiple loci, the Genetic Analysis Workshop 12 general population simulated data set was analyzed using variance component methods. Using the described novel selection criteria resulted in an increase of power, however, a rejection of the null hypothesis has to be interpreted with care.

Analysis of Variance↗
PubMed2001

Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia.

Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08-6.46 cM critical interval on 9p13.3-12 in the region of autosomal recessive IBM2.

Adult↗