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At least 559 records · Page 31Linked to original sources
PubMed1999

[Gene diagnosis of X linked retinitis pigmentosa by linkage analysis].

OBJECTIVE: To establish a gene diagnosis method for X linked retinitis pigmentosa (XLRP). METHODS: Ten microsatellite markers were selected from the region where the RP2 and RP3 gene may be located at Xp21.1-p11.23. Haplotype analysis for XLRP pedigrees was used to determine the chromosome region which is RP related and whether this region was carried by the individuals we want to detect. RESULTS: The young female who is the RP carrier or the young boy who is the pre-symptom RP patient could be determined this way in 4 XLRP family. CONCLUSION: Haplotype analysis for XLRP Pedigrees is useful.

Adult↗
PubMed2001

Lewy bodies and parkinsonism in families with parkin mutations.

Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early-onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early-onset Parkinson's disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2-27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early-onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.

Adult↗
PubMed2006

Association study of polymorphisms in post-synaptic density protein 95 (PSD-95) with schizophrenia.

The postsynaptic density protein 95 (PSD-95) - the prototype of this family - is a modular protein that enables anchoring of NMDA receptors, modulates NMDA receptor sensitivity to glutamate and coordinates NMDA receptor-related intracellular processes. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, we explored the hypothesis that genetic variants of the PSD-95 gene were associated with a diagnosis of schizophrenia. Three PSD-95 polymorphisms were studied in a sample population of 248 people with schizophrenia and 208 normal controls. One polymorphism (rs373339) was not informative in our Chinese population while the other two polymorphisms (rs2521985 and rs17203281) were analysed with chi-square tests and haplotype analysis. Results demonstrated that the two informative polymorphisms are in strong linkage disequilibrium with each other. Neither single marker nor haplotype analysis revealed an association between variants at the PSD-95 locus and schizophrenia, suggesting that it is unlikely that the PSD-95 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further genetic studies in schizophrenia with other PSD-95-like molecules that interact with the glutamate system are suggested.

Adult↗
PubMed2004

Hereditary spastic paraplegia: clinical genetic study of 15 families.

BACKGROUND: Autosomal dominant hereditary spastic paraplegia (ADHSP) is mainly caused by mutations in the SPG4 gene, which encodes a new member of the AAA (adenosine triphosphatases associated with diverse cellular activities) protein family (spastin). Accumulation of genotype-phenotype correlation is important for better understanding of SPG4-linked hereditary spastic paraplegia. OBJECTIVES: To perform a clinical and genetic study of families with ADHSP and to perform the functional analysis of the founder mutation discovered in the SPG4 gene. DESIGN: Genetic and clinical study. Patients Fifteen unrelated families with ADHSP originating from southern Scotland. MAIN OUTCOME MEASURES: Clinical assessment, linkage analysis, haplotype study, expression of mutant spastin protein in cultured cells. RESULTS: Nine families with ADHSP were linked to the SPG4 locus at 2p21-p24. Sequence analysis of SPG4showed a novel N386S mutation in all 9 of these families. Expression of mutant spastin showed aberrant distribution in cultured cells. Haplotype analysis suggested the existence of a common founder. Clinical examination of the affected members carrying the mutation showed phenotypic variations including broad range of age at onset and disease duration and additional neurologic features such as mental retardation. Magnetic resonance imaging demonstrated unique features, including thin corpus callosum and atrophy of the cerebellum in 2 patients. Linkage and sequence analyses showed no evidence of linkage to the currently known ADHSP loci in the remaining 6 families. CONCLUSIONS: A founder SPG4 mutation N386S was identified in the families with ADHSP originating from southern Scotland. Clinical investigation showed intrafamilial and interfamilial phenotypic variations. The genetic study demonstrated evidence of further genetic heterogeneity in ADHSP.

Adenosine Triphosphatases↗
PubMed2005

Genome sequence, comparative analysis and haplotype structure of the domestic dog.

Here we report a high-quality draft genome sequence of the domestic dog (Canis familiaris), together with a dense map of single nucleotide polymorphisms (SNPs) across breeds. The dog is of particular interest because it provides important evolutionary information and because existing breeds show great phenotypic diversity for morphological, physiological and behavioural traits. We use sequence comparison with the primate and rodent lineages to shed light on the structure and evolution of genomes and genes. Notably, the majority of the most highly conserved non-coding sequences in mammalian genomes are clustered near a small subset of genes with important roles in development. Analysis of SNPs reveals long-range haplotypes across the entire dog genome, and defines the nature of genetic diversity within and across breeds. The current SNP map now makes it possible for genome-wide association studies to identify genes responsible for diseases and traits, with important consequences for human and companion animal health.

Animals↗
PubMed1996

Evidence for a common origin of most Friedreich ataxia chromosomes in the Spanish population.

Haplotype analysis is a powerful approach to understand the spectrum of mutations accounting for a disease in a homogeneous population. We show that haplotype variation for 10 markers linked to the Friedreich ataxia locus (FRDA) argues in favor of an important mutation homogeneity in the Spanish population, and positions the FRDA locus in the region where it has been recently isolated. We also report the finding of a new single nucleotide polymorphism called FAD1. The new marker shows a very strong linkage disequilibrium with Friedreich ataxia (FA) in both the Spanish and French populations. suggesting the existence of an ancient and widespread FRDA mutations. Inclusion of FAD1 in the extended haplotype analysis has allowed to postulate that this main FRDA mutation could account for 50-90% of the disease chromosomes. The results indicate that FA, despite clinical heterogeneity, could have originated from a few initial mutations.

Adaptor Proteins, Signal Transducing↗
PubMed2004

X-linked high myopia associated with cone dysfunction.

OBJECTIVE: Bornholm eye disease (BED) consists of X-linked high myopia, high cylinder, optic nerve hypoplasia, reduced electroretinographic flicker with abnormal photopic responses, and deuteranopia. The disease maps to chromosome Xq28 and is the first designated high-grade myopia locus (MYP1). We studied a second family from Minnesota with a similar X-linked phenotype, also of Danish descent. All affected males had protanopia instead of deuteranopia. METHODS: X chromosome genotyping, fine-point mapping, and haplotype analysis of the DNA from 22 Minnesota family individuals (8 affected males and 5 carrier females) and 6 members of the original family with BED were performed. Haplotype comparisons and mutation screening of the red-green cone pigment gene array were performed on DNA from both kindreds. RESULTS: Significant maximum logarithm of odds scores of 3.38 and 3.11 at theta = 0.0 were obtained with polymorphic microsatellite markers DXS8106 and DXYS154, respectively, in the Minnesota family. Haplotype analysis defined an interval of 34.4 cM at chromosome Xq27.3-Xq28. Affected males had a red-green pigment hybrid gene consistent with protanopia. We genotyped Xq27-28 polymorphic markers of the family with BED, and narrowed the critical interval to 6.8 cM. The haplotypes of the affected individuals were different from those of the Minnesota pedigree. Bornholm eye disease-affected individuals showed the presence of a green-red hybrid gene consistent with deuteranopia. CONCLUSIONS: Because of the close geographic origin of the 2 families, we expected affected individuals to have the same haplotype in the vicinity of the same mutation. Mapping studies, however, suggested independent mutations of the same gene. The red-green and green-red hybrid genes are common X-linked color vision defects, and thus are unrelated to the high myopia and other eye abnormalities in these 2 families. CLINICAL RELEVANCE: X-linked high myopia with possible cone dysfunction has been mapped to chromosome Xq28 with intervals of 34.4 and 6.8 centimorgan for 2 families of Danish origin.

Adolescent↗
PubMed1991

Extended HLA-DQw2 haplotypes: molecular analysis.

The HLA-DQw2 specificity, homogeneous in serology, is strongly associated to two HLA-DR specificities: DR3 and DR7. These alleles are found mainly on DQw2 bearing extended haplotypes with strong linkage disequilibrium. We describe, with BamHI, HindIII and RsaI, two restriction fragments length polymorphisms (RFLP) for the A gene of DQw2. These two subtypes correlated with the DR3 and DR7 specificities. Interestingly, by non-equilibrium pH gradient electrophoresis (NEPHGE), two DQ alpha chains were also found, respectively correlated with the same DR specificities. In addition, HincII polymorphism allowed us to distinguish several patterns of B genes for (DR7) DQw2 haplotypes but without any detectable association with another HLA marker. However, only one DQ beta chain was found by NEPHGE in the (DR7) DQw2 haplotype. Furthermore, HincII discriminated the B genes of the two extended haplotypes: (B8, DR3) DQw2 and (B18, DR3) DQw2. The same result was found by NEPHGE: two DQ beta chains were described, corresponding to the same extended haplotypes. The use of exon-specific DQB probes showed that the genomic polymorphism in DQw2 haplotypes is located, at least, at the 3' end of the gene. These data add new characteristics to the different DQw2 extended haplotypes.

Cell Line↗
PubMed1998

[Gene diagnosis and genetic counselling of Rb gene mutations in retinoblastoma patients and their family members].

OBJECTIVE: To develop a diagnostic test for direct identification of disease-causing mutation in the patients with retinoblastoma and correct prediction of carrier- status in unaffected adults and newborns in the RB kindred. METHODS: Southern blot hybridized by Rb cDNA and other intragenic probes were used to detect big deletions or rearrangements at Rb gene locus. SSCP analysis and direct sequencing of primer-directed enzymatic amplification to identify point mutations as small as a single nucleotide change. RFLPs and VNTRs within the Rb gene were used as genetic markers for haplotype analysis. RESULTS: The probands from 79 RB kindreds were identified to have Rb gene mutation, including 25 somatic mutations and 54 germline mutations (36 new germline mutations, 15 inherited mutations and 3 mosaicisms). The WBC DNAs from their family members were also analyzed for determining origin and carrier of mutation. CONCLUSION: The direct identification of causing- cancer mutations by combining SSCP analysis and direct DNA sequencing showed many advantages than other indirect methods such as haplotype analysis. It can distinguish hereditary RB from nonhereditary RB and identify the unaffected carriers without family history and informes affected family member. This method is helpful in gene diagnosis and genetic counselling.

Adult↗
PubMed2000

The BRCA2 genetic variant IVS7 + 2T-->G is a mutation.

Biochemical and genetic characterizations that support the conclusion that the variant BRCA2 IVS7 + 2T --> G represents a deleterious mutation are presented. RNA analysis from a breast cancer patient with BRCA2 IVS7 + 2T --> G showed that the productive message was produced from only one chromosome. A haplotype analysis confirmed that the intronic variant resides on the chromosome that does not produce the normal mRNA. Additionally, an RNA splicing product that deletes exon 7 was produced by the chromosome that carries BRCA2 IVS7 + 2T --> G. The deletion of exon 7 from the RNA alters the open reading frame by removing residues 249-287 and incorporating 18 abnormal amino acids before terminating with an opal stop codon. The experimental approach presented produces strong evidence of the presence of a deleterious mutation, because the contribution by both chromosomes to each RNA species analyzed was tracked using a coding region polymorphism as a marker. Furthermore, a single nucleotide polymorphism (SNP) haplotype analysis that confirms the location of the intronic variant and an associated family history that shows a high incidence of cancer supported these biochemical data.

5' Untranslated Regions↗
PubMed1997

Haplotype sharing analysis in affected individuals from nuclear families with at least one affected offspring.

In diseases with a complex mode of inheritance, families with multiple affected individuals are difficult to ascertain. The haplotype sharing statistic (HSS) uses (hidden) co-ancestry between affected individuals from a founder population. These affected individuals will likely not only share the same mutation(s), but also the surrounding haplotype. We show that this method gives a low false positive rate, but does not detect genes in the nuclear families of Problem 2A of the GAW data. We also give evidence based on simulations and empirical studies in real population based data that the HSS method has statistical power.

Chromosome Mapping↗
PubMed2004

Common variation in BRCA2 and breast cancer risk: a haplotype-based analysis in the Multiethnic Cohort.

It is well established that rare mutations in BRCA2 predispose to familial breast cancer, but whether common variants at this locus contribute more modest risk to sporadic breast cancer has not been thoroughly investigated. We performed a haplotype-based study of BRCA2 among women in the Multiethnic Cohort Study (MEC), genotyping 50 SNPs spanning 109.4 kb of the BRCA2 gene. Twenty-one haplotype-tagging SNPs (including seven missense SNPs) were selected to predict the common BRCA2 haplotypes and were genotyped in a breast cancer case-control study nested in the MEC (cases, n=1715; controls, n=2502). Compared to non-carriers, we observed nominally significant positive associations for homozygous carriers of specific haplotypes in blocks 2 (haplotype 2c: OR=1.50; 95% CI, 1.08-2.09) and 3 (haplotype 3d: OR=1.50; 95% CI, 1.01-2.24). These results could be explained on the basis of a single marker in intron 24 (SNP 42: rs206340) that was correlated with these haplotypes and the homozygous state was associated with a significantly increased risk of breast cancer (AA versus GG genotypes: OR=1.59, 95% CI, 1.18-2.16; nominal P=0.005). This association was modestly stronger among women with advanced disease (OR=2.00, 95% CI, 1.30-3.08; P=0.002). In this exploratory analysis, we found little indication that common variation in BRCA2 dramatically impacts sporadic breast cancer risk. However, a significant elevation in risk was observed among approximately 6% of women who carried a specific haplotype pattern and may harbor a susceptibility allele at the BRCA2 locus.

Aged↗
PubMed2003

AACR Special Conference: SNPs, haplotypes, and cancer - applications in molecular epidemiology, Key Biscayne, Florida, USA, 13-17 September 2003.

This American Association for Cancer Research Special Conference brought together scientists with diverse expertise to address issues related to use of appropriate epidemiological, statistical, and laboratory methods to study the genetic epidemiology of cancer. Discussions focused on experiences with association studies using single nucleotide polymorphisms and haplotypes, their limitations, and what is needed to improve on the current 'state of the art'. Various studies were presented in different contexts, ranging from candidate gene studies to whole genome scans, and conducted in prospective cohorts, case-control studies, and other study designs. Common problems such as determining the probability that observed associations are false negative or false positive, the potential effects of admixture, and determining which polymorphisms to examine in which genes and in which populations were examined. Problems specific to haplotype analysis were discussed, with emphasis on haplotype block structures and on how to use haplotypes in analysis. Questions were also posed as to determining the functional relevance of single nucleotide polymorphisms in molecular epidemiology. Finally, future directions, using specific examples, were addressed.

DNA, Neoplasm↗
PubMed1997

Familial defective apolipoprotein B-100 in hypercholesterolemic Chinese Canadians: identification of a unique haplotype of the apolipoprotein B-100 allele.

Familial defective apo B-100 (FDB) is an autosomal dominant condition resulting in hypercholesterolemia. It is generally observed in 1-6% of hypercholesterolemic subjects in Caucasian populations studied. There are, thus far, no reports characterizing the frequency and phenotype of FDB in a Chinese population. We report on the frequency of the FDB (Arg(3500)--> Gln) mutation and the associated haplotype among 160 hypercholesterolemic (TC > or = 6.2 mmol/l) Chinese Canadians including 36 subjects with a clinical diagnosis of familial hypercholesterolemia (FH). Screening for the FDB mutation was done using a mutagenic polymerase chain reaction and haplotype analysis was undertaken using eight diallelic markers and the 3'HVR marker. One Chinese Canadian clinical FH heterozygote was positive for the FDB Arg(3500)--> Gln mutation while none of the remaining non-FH hypercholesterolemic subjects (n = 124) were carriers of this mutation. Haplotype analysis in the patient positive for this mutation revealed a unique haplotype which differed from both the common haplotype of this mutation observed in Caucasians and from the only other haplotype reported in a Chinese individual. The associated haplotype included a 9-base pair deletion in the signal peptide region and the presence of three restriction sites absent in previously reported haplotypes. These data suggest that the apo B-100 Arg(3500)--> Gln mutation does not appear to be a significant factor contributing to moderate hypercholesterolemia in a Chinese population residing in Canada. However, this mutation was rarely observed among Chinese individuals with a clinical diagnosis of FH. The presence among Chinese individuals of two different haplotypes associated with this mutation, which are different from what has been described among Caucasians is compatible with multiple recurrent origins for this mutation in the Chinese population.

Adolescent↗
PubMed2004

[Carrier detection of Duchenne/Becker muscular dystrophy in Chinese families by microsatellite analysis].

OBJECTIVE: To screen and detect the female carriers from the DMD/BMD family members for prenatal or preimplantation genetic diagnosis. METHODS: For the detection of DMD/BMD carriers from 27 family members in 4 families, PCR to five microsatellite markers(located in 5' terminus and intron 44, 45, 49, 50) and analysis of the short tandem repeat(STR) sequence polymorphism with the use of genescan were implemented. RESULTS: Six of the 17 female members were obligate DMD gene carriers according to the haplotype analysis of the results of the genescan, which conformed with the pedigree analysis. Besides, the authors detected five carriers and five normal females in these families with the use of the haplotype analysis only. The most polymorphic locus was STR 49, and the least was STR 50. CONCLUSION: The STR haploid linkage analysis using (CA)n repeats within the human dystrophin gene is a rapid,accurate, objective method and is well suited for routine use in clinical laboratories engaged in DMD/BMD linkage analysis for the detection of carrier.

Female↗
PubMed2004

Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.

The IGF2-INS-TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51-62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.

Aged↗
PubMed2005

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Black or African American↗
PubMed1999

Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families.

OBJECTIVE: To report the phenotype associated with the codon 172 RDS (gene for retinal degeneration slow) mutation in 11 separate families with an arginine-to-tryptophan substitution with common ancestry, and 1 family with an arginine-to-glutamine transition. PATIENTS: Screening for RDS gene mutations was performed in 400 subjects with autosomal dominant retinal degeneration. Twelve families were identified with a mutation in codon 172. Haplotype analysis was performed. Full ophthalmic evaluation was performed, including electrophysiologic and psychophysical investigation and imaging of autofluorescence using confocal laser scanning ophthalmoscopy. RESULTS: Haplotype analysis demonstrated that the 11 families were ancestrally related. All 12 families showed a common phenotype of macular dysfunction, with the deficit increasing with age. Abnormally high autofluorescence predated loss of visual acuity or visual field changes. Pattern electroretinographic (PERG) findings were affected early in disease. There was high intrafamilial and interfamilial consistency of phenotype. CONCLUSION: These families demonstrate a striking conformity of symptoms and signs. CLINICAL RELEVANCE: In the codon 172 RDS mutation, unlike disease resulting from other RDS mutations, prediction of approximate age of onset and progression of visual deficit is possible. This should assist diagnosis and counseling.

Adolescent↗