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Biomedical subjects

M M Barmada

Publications and source records attributed to M M Barmada.

15 recordsLinked to original sources
PubMed2005

The SPINK1 N34S mutation is not associated with Type 2 diabetes mellitus in a population of the USA.

AIMS: Mutations in the serine protease inhibitor (SPINK1) gene have been associated with all forms of chronic pancreatitis. Recently, an association of SPINK1 mutations with early-onset Type 2 diabetes mellitus has been reported in patients from Bangladesh. Therefore, we determined the frequency of SPINK1 N34S mutations in patients with Type 2 diabetes mellitus from the USA. METHODS: The study population of Hispanic and non-Hispanic white people consisted of 387 patients with Type 2 diabetes and familial clustering of the disease, 232 family members without diabetes, 259 patients with Type 2 diabetes without a family history, and 302 ethnically matched healthy controls as part of the San Luis Valley Diabetes Study. We performed linkage- and association-analysis in 82 multiplex families with Type 2 diabetes mellitus. RESULTS: No significant linkage or allele sharing was detected between Type 2 diabetes mellitus and the SPINK1 locus. The frequency of the N34S mutation was determined by fluorescence polarization and was similar between patients (n = 14/387 patients with familial clustering; n = 2/259 patients without family history) and controls (n = 5/232 family members without diabetes; n = 10/302 individuals). Variables such as ethnicity, age of diabetes onset and percentage of individuals with impaired glucose tolerance did not differ significantly between carriers and homozygous normal individuals. CONCLUSION: The SPINK1 N34S mutation appears not to predispose Hispanic or non-Hispanic white people from the USA to the development of Type 2 diabetes mellitus.

Chronic Disease↗
PubMed2002

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.

INTRODUCTION: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. AIM: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. METHODS: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). RESULTS: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. CONCLUSION: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Alleles↗
PubMed2001

Model-free linkage analysis: performance under real-world conditions.

The simulated data of the Genetic Analysis Workshop 12 problem set affords an ideal environment for testing real-world performance of model-free linkage analysis methods. To this end, we applied three different methods of model-free linkage analysis: mod scores [Hodge and Elston, Genet Epidemiol 11:329-42, 1994], maximized maximum lod score (MMLS) [Greenberg et al., Am J Hum Genet 63:870-9, 1998], and nonparametric linkage (NPL) scores [Whittemore and Halpern, Biometrics 50:118-27, 1994], as well as standard parametric linkage analysis to the detection of major gene 6 (MG6) using only the qualitative disease status data. Our results indicate that both mod scores and NPL scores perform well, even in the presence of an extremely complicated disease model. MMLS analysis did not perform well, except at the disease locus itself.

Chromosome Mapping↗
PubMed2000

The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease.

The IBD2 locus on chromosome 12 has been linked to both Crohn disease (CD) and ulcerative colitis (UC) but has not been detected in some CD-dominated data sets. In the present study, we genotyped 581 relative pairs with inflammatory bowel disease (252 from CD-only families, 138 from UC-only families, and 191 from mixed families containing cases of both CD and UC), using 12 markers spanning the IBD2 locus. A GENEHUNTER-PLUS multipoint LOD score of 3.91 was detected for pairs from UC-only families, compared with 1.66 for CD-only and 1.29 for mixed families. The difference between the LOD scores for UC and CD was significant in two different tests for heterogeneity (P=.0057 for one test and P=.0375 for the other). IBD2 thus appears to make a major contribution to UC susceptibility but to have only a relatively minor effect with regard to CD, for which there may be substantially more locus heterogeneity.

Alleles↗
PubMed2000

High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11-12.

Epidemiological studies have shown that genetic factors contribute to the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD) and ulcerative colitis (UC). Recent genome scans and replication studies have identified replicated linkage between CD and a locus on chromosome 16 (the IBD1 locus), replicated linkage between IBD (especially UC) and a locus on chromosome 12q (the IBD2 locus), and replicated linkage between IBD (especially CD) and a locus on chromosome 6p (the IBD3 locus). Since the estimated locus-specific lambdas values for the regions of replicated linkage do not account for the overall lambdas in CD, and since the published genome scans in IBD show at least nominal evidence for linkage to regions on all but two chromosomes, we performed an independent genome scan using 751 microsatellite loci in 127 CD-affected relative pairs from 62 families. Single-point nonparametric linkage analysis using the GENEHUNTER-PLUS program shows evidence for linkage to the adjacent D14S261 and D14S283 loci on chromosome 14q11-12 (LOD = 3.00 and 1.70, respectively), and the maximal multipoint LOD score is observed at D14S261 (LOD = 3.60). In the multipoint analysis, nominal evidence for linkage (P<.05) is observed near D2S117 (LOD = 1.25), near D3S3045 (LOD = 1.31), between D7S40 and D7S648 (LOD = 0.91), and near D18S61 (LOD = 1.15). Our finding of significant linkage to D14S261 and the finding of suggestive linkage to the same locus in an independent study (multipoint LOD = 2.8) satisfies criteria for confirmed linkage, so we propose that the region of interest on chromosome 14q11-12 should be designated the IBD4 locus.

Chromosome Mapping↗
PubMed2000

SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis.

BACKGROUND & AIMS: Gain-of-function trypsin mutations cause acute pancreatitis and chronic pancreatitis. Loss of trypsin inhibitor function may have similar effects. We investigated the prevalence of SPINK1 (PSTI) mutations in familial pancreatitis, idiopathic chronic pancreatitis, and controls. METHODS: Genetic-linkage studies were performed in 5 familial pancreatitis families. The entire SPINK1 gene was sequenced in 112 affected individuals and 95 control DNA samples, and exon 3 was sequenced in 95 additional controls. X-ray crystallography-based model building and statistical studies were performed. RESULTS: Significant linkage between pancreatitis and 5q31.1-2 was excluded. Novel SPINK1 mutations, one D50E mutation, one IVS3+125 C>A, and five IVS3+184 T>A intronic polymorphisms were identified. The N34S and P55S mutations were observed in 29 of 112 patients (25%) as N34S/N34S (n = 7), N34S/wt (n = 19), N34S/P55S (n = 2), and N34S/D50E (n = 1). Three hundred eighty control alleles revealed 3 N34S (0.77%), 2 P55S (0.53%), and no D50E mutations. Age of disease onset and severity were similar between homozygous and heterozygous patients. Structural modeling revealed several possible pathophysiologic mechanisms for the N34S mutation. CONCLUSIONS: SPINK1 mutations are common in the population (approximately 2%), but are clearly associated with pancreatitis. The mutation-associated risk is low. Modeling and familial clustering suggest that SPINK1 mutations are disease modifying, possibly by lowering the threshold for pancreatitis from other genetic or environmental factors, but by themselves do not cause disease.

Amino Acid Sequence↗
PubMed1999

Genetic heterogeneity of dominant optic atrophy, Kjer type: Identification of a second locus on chromosome 18q12.2-12.3.

OBJECTIVE: To evaluate a family with autosomal dominant optic atrophy, which has been previously linked to the Kidd blood group. DESIGN: Clinical evaluation with the assessment of visual acuity, color vision, and optic nerve appearance to determine affection status. Linkage analysis using polymorphic DNA markers. RESULTS: Visual acuities ranged from 20/20 to 6/200. Although linkage was excluded for chromosome 3q28-29, markers from chromosome 18 in the vicinity of the Kidd locus were linked to the disorder (D18S34 [maximal lod score (lodmax) of 5.38 at recombination fraction (theta) of 0.14], D18S548 [lod(max)=7.26, theta=0.09], D18S861 [lod(max)= 5.32, theta = 0.07], and D18S479 [lod(max) = 3.28, 0 = 0.12:]). Multipoint linkage analysis demonstrated lod scores of greater than 3 in an approximately 3-centimorgan region flanked by D18S34 and D18S479, using 98% penetrance and a phenocopy rate of 1/50. CONCLUSIONS: Dominant optic atrophy is genetically heterogeneous, with loci assigned to chromosomes 3q28-29 and 18q12.2-12.3. Dominant optic atrophy linked to 18q shows intrafamilial variation similar to that previously reported in families linked to 3q, with visual acuities ranging from normal to legal blindness. The overall distribution of visual acuities appears more favorable with the 18q phenotype. Both phenotypes appear to have a similar rate of visual decline.

Adolescent↗
PubMed1999

A simple allele sharing statistic for multiple locus systems.

For complex disorders where the actions of several interacting loci must be taken into account, current methods of joint linkage analysis are problematic. We have undertaken an exploration of simultaneous search statistics originally proposed by Dupuis et al. [1995]. Additionally, we have extended these methods slightly and propose here a simple simultaneous search statistic based upon the single-point allele sharing statistic calculated from GENEHUNTER (GH). The use of conditional search techniques is also explored.

Alleles↗
PubMed1999

Congenital motor nystagmus linked to Xq26-q27.

Congenital motor nystagmus (CMN) is a hereditary disorder characterized by bilateral ocular oscillations that begin in the first 6 mo of life. It must be distinguished from those genetic disorders-such as ocular albinism (OA), congenital stationary night blindness (CSNB), and blue-cone monochromatism (BCM)-in which nystagmus accompanies a clinically apparent defect in the visual sensory system. Although CMN is presumed to arise from a neurological abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Three families with CMN inherited in an X-linked, irregularly dominant pattern were investigated with linkage and candidate gene analysis. The penetrance among obligate female carriers was 54%. Evaluation of markers in the region of the genes for X-linked OA, CSNB, and BCM revealed no evidence of linkage, supporting the hypothesis that CMN represents a distinct entity. The gene was mapped to chromosome Xq26-q27 with the following markers: GATA172D05 (LOD score 3.164; recombination fraction [theta] = 0.156), DXS1047 (LOD score 10.296; theta = 0), DXS1192 (LOD score 8.174; theta = 0.027), DXS1232 (LOD score 6.015; theta = 0.036), DXS984 (LOD score 6.695; theta = 0), and GATA31E08 (LOD score 4.940; theta = 0.083). Assessment of haplotypes and multipoint linkage analysis, which gave a maximum LOD score of 10.790 with the 1-LOD-unit support interval spanning approximately 7 cM, place the gene in a region between GATA172D05 and DXS1192. Evaluation of candidate genes CDR1 and SOX3 did not reveal mutations in affected male subjects.

Female↗
PubMed1998

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.

Chromosomes, Human, Pair 12↗
PubMed1998

Hereditary lymphedema: evidence for linkage and genetic heterogeneity.

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.

Chromosomes, Human, Pair 5↗
PubMed1997

A new locus for hemiplegic migraine maps to chromosome 1q31.

A single familial hemiplegic migraine locus has been previously mapped to 19p13.1 and associated with mutations in a calcium channel gene (CACNL1A4). We describe a new 39-member four-generation family from Wyoming of German-Native American descent with autosomal dominant familial hemiplegic migraine that is not linked to the chromosome 19p locus. Affected individuals showed a stereotypic pattern of migrainous headache associated with hemisensory and hemiparetic attacks, without other headache types. Eighty-three percent reported minor head trauma as a trigger for individual attacks. Seventy-two percent reported other typical migraine triggers for the attacks. Attack frequency decreased with age and the overall course was benign. Genetic linkage studies of this family found strong evidence for the disease gene in this family being located at chromosome 1q31. Multipoint analysis showed lod scores > 3 in a 44-cm region flanked by D1S158 and D1S2781, using 80% penetrance and a phenocopy rate of 1/50. Haplotype and multipoint analysis, including flanking markers, suggested incomplete penetrance and variable expressivity of the disease. A single affected patient who reports atypical symptoms including daily headaches likely represents a phenocopy. This new locus for hemiplegic migraine suggests that mutations of additional calcium channels in the region may cause the disease.

Adolescent↗
PubMed1996

A gene for autosomal dominant congenital nystagmus localizes to 6p12.

Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at theta = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor nystagmus to an 18-cM region between D6S271 and D6S455.

Chromosome Mapping↗