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1.
Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC) 总被引:1,自引:1,他引:1
Kelsell DP; Risk JM; Leigh IM; Stevens HP; Ellis A; Hennies HC; Reis A; Weissenbach J; Bishop DT; Spurr NK; Field JK 《Human molecular genetics》1996,5(6):857-860
Focal non-epidermolytic palmoplantar keratoderma (PPK or palmoplantar
ectodermal dysplasia type III) is associated with oesophageal cancer in
three families: two large pedigrees located in Liverpool, UK and in the
midwestern American states and one smaller family from Germany. In these
families, the PPK is inherited as autosomal dominant and has a late onset,
usually manifesting between 7 and 8 years of age. The disease is
characterised by thickening of the pressure areas of the soles, but is not
restricted to the feet and also presents with oral leukokeratosis and
follicular hyperkeratosis. The disease locus [previously termed the
"tylosis oesophageal cancer gene' (TOC) locus] has been mapped to
17q23-qter by linkage analysis. This region is located telomeric to the
keratin 16 gene, in which mutations have been identified in focal PPK
families who show no increased cancer risk. We describe the close mapping
of this locus to the interval between AFMb054zf9 and D17S1603 using
haplotype analysis of additional Genethon markers in the region and show
that although the American family is unlikely to be related to either of
the other two, the UK and German pedigrees may share a common descent. This
work provides a basis for positional cloning and candidate gene analysis in
order to identify a gene that may be involved in familial oesophageal
cancer.
相似文献
2.
Genetic variability in the regulatory region of presenilin 1 associated with risk for Alzheimer's disease and variable expression 总被引:8,自引:0,他引:8
Theuns J Del-Favero J Dermaut B van Duijn CM Backhovens H Van den Broeck MV Serneels S Corsmit E Van Broeckhoven CV Cruts M 《Human molecular genetics》2000,9(3):325-331
3.
Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1 总被引:10,自引:0,他引:10
Lemmens I; Van de Ven WJ; Kas K; Zhang CX; Giraud S; Wautot V; Buisson N; De Witte K; Salandre J; Lenoir G; Pugeat M; Calender A; Parente F; Quincey D; Gaudray P; De Wit MJ; Lips CJ; Hoppener JW; Khodaei S; Grant AL; Weber G; Kytola S; Teh BT; Farnebo F; Thakker RV 《Human molecular genetics》1997,6(7):1177-1183
4.
Frequent genetic and epigenetic abnormalities contribute to the deregulation of cytoglobin in non-small cell lung cancer 总被引:2,自引:0,他引:2
Xinarianos G McRonald FE Risk JM Bowers NL Nikolaidis G Field JK Liloglou T 《Human molecular genetics》2006,15(13):2038-2044
Lung cancer demonstrates the highest mortality in the UK. Previous studies have implicated allelic loss at chromosome 17q in the development of non-small cell lung carcinoma (NSCLC), and a number of known and putative tumour-suppressor genes reside within this region. One candidate tumour-suppressor gene is cytoglobin (CYGB), which is contained entirely within the 42.5 kb tylosis with oesophageal cancer (TOC) minimal region. CYGB abnormalities have been demonstrated only in sporadic head and neck cancers. In this study, we investigated the expression, promoter methylation and allelic imbalance status of this gene in 52 paired (normal/tumour) surgically excised lung tissue samples from patients with NSCLC. CYGB expression in tumour tissue was significantly reduced compared with corresponding adjacent normal in 54% of the examined cases (paired t-test, P<0.001). The CYGB promoter was shown by pyrosequencing to be significantly hypermethylated [2-fold increase of methylation index (MtI) in tumours] in 25/52 (48%) tumour samples compared with normal samples. MtI of the CYGB promoter was associated with CYGB mRNA expression (linear regression analysis, P=0.009), suggesting a primary role for the epigenetic events in CYGB silencing. In addition, frequent LOH was detected at the locus 17q25 in 32/48 (67%) tumours examined. It is of note that the loss of expression intensified when both LOH and hypermethylation coincided in samples (Mann-Whitney, P=0.049). These findings provide the first evidence to suggest the implication of CYGB in the pathogenesis of NSCLCs. 相似文献
5.
Cryns K Sivakumaran TA Van den Ouweland JM Pennings RJ Cremers CW Flothmann K Young TL Smith RJ Lesperance MM Van Camp G 《Human mutation》2003,22(4):275-287
WFS1 is a novel gene and encodes an 890 amino-acid glycoprotein (wolframin), predominantly localized in the endoplasmic reticulum. Mutations in WFS1 underlie autosomal recessive Wolfram syndrome and autosomal dominant low frequency sensorineural hearing impairment (LFSNHI) DFNA6/14. In addition, several WFS1 sequence variants have been shown to be significantly associated with diabetes mellitus and this gene has also been implicated in psychiatric diseases. Wolfram syndrome is highly variable in its clinical manifestations, which include diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Wolfram syndrome mutations are spread over the entire coding region, and are typically inactivating, suggesting that a loss of function causes the disease phenotype. In contrast, only non-inactivating mutations have been found in DFNA6/14 families, and these mutations are mainly located in the C-terminal protein domain. In this paper, we provide an overview of the currently known disease-causing and benign allele variants of WFS1 and propose a potential genotype-phenotype correlation for Wolfram syndrome and LFSNHI. 相似文献
6.
Harada H Nagai H Mine N Terada Y Fujiwara H Mikami I Tsuneizumi M Yabe A Miyazaki K Yokota T Imoto I Inazawa J Emi M 《Journal of human genetics》2001,46(2):70-75
Human cancers derived from breast, esophageal, or ovarian tissues frequently show allelic losses on chromosome band 17q25.
Moreover, a locus responsible for hereditary focal nonepidermolytic palmoplantar keratoderma, a condition associated with
esophageal cancer (TOC; tylosis with oesophageal cancer), has been mapped to the same band. During efforts to sequence, by
shotgun methods, a 1-Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s)
involved in these events, we identified a novel cDNA. The full-length cDNA is 2495 bp long and is expressed predominantly
in skeletal muscle, heart, kidney, and placenta. The predicted product, a 627-amino-acid protein, exhibited significant sequence
homology to the canine 68-kd subunit of the signal recognition particle that has been implicated in the transport of secreted
and membrane proteins to the endoplasmic reticulum for proper processing. We confirmed the location of this gene at chromosome
17q25.1 by radiation-hybrid mapping and by fluorescence in situ hybridization.
Received: September 18, 2000 / Accepted: November 10, 2000 相似文献
7.
Structural variants (SVs) are an important source of human genome diversity, but their functional effects are poorly understood. We mapped 61,668 SVs in 613 individuals from the GTEx project and measured their effects on gene expression. We estimate that common SVs are causal at 2.66% of eQTLs, a 10.5-fold enrichment relative to their abundance in the genome. Duplications and deletions were the most impactful variant types, whereas the contribution of mobile element insertions was small (0.12% of eQTLs, 1.9-fold enriched). Multitissue analysis of eQTLs revealed that gene-altering SVs show more constitutive effects than other variant types, with 62.09% of coding SV-eQTLs active in all tissues with eQTL activity compared with 23.08% of coding SNV- and indel-eQTLs. Noncoding SVs, SNVs and indels show broadly similar patterns. We also identified 539 rare SVs associated with nearby gene expression outliers. Of these, 62.34% are noncoding SVs that affect gene expression but have modest enrichment at regulatory elements, showing that rare noncoding SVs are a major source of gene expression differences but remain difficult to predict from current annotations. Both common and rare SVs often affect the expression of multiple genes: SV-eQTLs affect an average of 1.82 nearby genes, whereas SNV- and indel-eQTLs affect an average of 1.09 genes, and 21.34% of rare expression-altering SVs show effects on two to nine different genes. We also observe significant effects on rare gene expression changes extending 1 Mb from the SV. This provides a mechanism by which individual SVs may have strong or pleiotropic effects on phenotypic variation.Structural variants (SVs) are a diverse class of genetic variation that include copy number variants (CNVs), mobile element insertions (MEIs), and balanced rearrangements at least 50 bp in length. Although SVs are relatively rare compared with single-nucleotide variants (SNVs) and small insertion or deletion (indel) variants, their size and diversity mean that SVs can disrupt protein-coding genes and genomic regulatory elements through diverse mechanisms. Furthermore, SVs often have more severe consequences compared with smaller variants, and previous studies have found that SVs have an outsized impact on human gene expression compared with their relative abundance in the genome (Stranger et al. 2007; Sudmant et al. 2015; Chiang et al. 2017). SVs have also been implicated in the biology of human diseases such as autism spectrum disorder (Sebat et al. 2007; Weiss et al. 2008; Turner et al. 2017; Brandler et al. 2018) and schizophrenia (International Schizophrenia Consortium 2008; Walsh et al. 2008; McCarthy et al. 2009; Marshall et al. 2017). However, SVs are difficult to detect from short-read DNA sequencing data and are often excluded from complex trait association studies.Advances in high-throughput sequencing technologies that have allowed for widespread use of whole-genome sequencing (WGS), combined with advances in scaling SV detection algorithms, mean that comprehensive studies of all forms of genetic variation are now possible for large human cohorts. Recent studies of SV in large, deeply sequenced human cohorts have found that SVs account for 4.0%–11.2% of rare high-impact coding alleles (Abel et al. 2020) and are responsible for 25%–29% of rare protein-truncating events per genome (Collins et al. 2020). However, few studies to date have examined the functional effects of SV on gene expression, and these studies are limited to relatively small cohort sizes or only a few tissue types with available gene expression data (Sudmant et al. 2015; Chiang et al. 2017; Han et al. 2020; Jakubosky et al. 2020).Here, we use deep WGS data and multitissue RNA-seq expression data from 613 individuals in the Genotype-Tissue Expression (GTEx) project to comprehensively map SVs and to evaluate their impact on both common and rare gene expression changes in up to 48 tissue types (Supplemental Table S1). This study expands on our prior analysis of SV in 147 human samples from the GTEx cohort with RNA-seq expression data from 13 different tissues (Chiang et al. 2017) and is the most comprehensive study of SV-eQTLs to date. The expanded cohort size provides greater power to evaluate the impact and mechanisms of SV-associated gene expression changes, particularly for rare SVs. 相似文献
8.
9.
An autosomal dominant posterior polar cataract locus maps to human chromosome 20p12-q12 总被引:4,自引:0,他引:4
Yamada K Tomita H Yoshiura K Kondo S Wakui K Fukushima Y Ikegawa S Nakamura Y Amemiya T Niikawa N 《European journal of human genetics : EJHG》2000,8(7):535-539
We assigned the locus for a previously reported new type of autosomal dominant posterior polar cataract (CPP3) to 20p12-q12 by a genome-wide two-point linkage analysis with microsatellite markers. CPP3 is characterized by progressive, disc-shaped, posterior subcapsular opacity. The disease was seen in 10 members of a Japanese family and transmitted in an autosomal dominant fashion through four generations. We obtained a maximum lod score (Zmax) of 3.61 with a recombination fraction (theta) of 0.00 for markers D20S917, D20S885 and D20S874. Haplotype analysis gave the disease gene localization at a 15.7-cM interval between D20S851 and D20S96 loci on chromosome 20p12-q12. Since the BFSP1 that encodes the lens-specific beaded filament structural protein 1 (filensin) has been mapped around the CPP3 region, we performed sequence analysis on its entire coding region. However, no base substitution or deletion was detected in the CPP3 patients. The mapping of the CPP3 locus to 20p12-q12 not only expands our understanding of the genetic heterogeneity in autosomal dominant posterior polar cataracts but also is a clue for the positional cloning of the disease gene. 相似文献
10.
Novelli A Valente EM Bernardini L Ceccarini C Sinibaldi L Caputo V Cavalli P Dallapiccola B 《European journal of human genetics : EJHG》2004,12(7):579-583
Brody disease is a rare muscle disorder characterized by exercise-induced impairment in muscle relaxation, due to a markedly reduced influx of calcium ions in the sarcoplasmic reticulum. A subset of autosomal recessive families harbour mutations in the ATP2A1 gene, encoding the fast-twitch skeletal muscle sarcoplasmic reticulum Ca(2+) ATPase (SERCA1). Rare autosomal dominant families have been described, in which ATP2A1 was excluded as the causative gene, further supporting genetic heterogeneity. We report four individuals from a three-generation Italian family with a clinical phenotype of Brody disease, in which linkage analysis excluded ATP2A1 as the responsible gene. The disease cosegregates in an autosomal dominant fashion with an apparently balanced constitutional chromosome translocation (2;7)(p11.2;p12.1), suggesting a causal relationship between the rearrangement and the phenotype. FISH analysis using YAC and PAC clones as probes refined the breakpoint regions to genomic segments of about 164 and 120 kb, respectively, providing a possible clue to pinpoint the location of a novel gene responsible for this rare muscle disorder. 相似文献
11.
S Lincoln R Crook M C Chartier-Harlin K Gwinn-Hardy M Baker V Mouroux F Richard E Becquet P Amouyel A Destée J Hardy M Farrer 《Neuroscience letters》1999,269(2):107-109
We present 11 families consistent with autosomal dominant inheritance of probable Parkinson's disease (PD). Although excluded as a cause of disease in these kindreds, mutations in the alpha-synuclein gene have been implicated in familial PD. The beta-synuclein gene is highly homologous, expressed in the nervous system and thus is a good candidate gene for PD. Multipoint linkage analysis was either equivocal or excluded 5q35 haplotype sharing among affected family members. Sequencing the translated exons of the beta-synuclein gene failed to identify any pathogenic mutation. 相似文献
12.
A large deletion including most of GJB6 in recessive non syndromic deafness: a digenic effect? 总被引:11,自引:0,他引:11
Pallares-Ruiz N Blanchet P Mondain M Claustres M Roux AF 《European journal of human genetics : EJHG》2002,10(1):72-76
Congenital profound deafness has a known genetic origin in more than 50% of all cases. The majority of the non syndromic hearing loss (NSHL) show an autosomal recessive inheritance. Mutations in the GJB2 gene (connexin 26) account for more than 50% of the recessive non syndromic deafness (DFNB1) among 30 loci. Other connexin genes have been more rarely involved and attention was given here to the GJB6 gene (connexin 30). We show that homozygous deletion of a minimal 150 kb region encompassing this gene causes NSHL. More strikingly, association of this deletion in trans of the GJB2 gene 35delG or E47X mutations is also associated with NSHL. 相似文献
13.
Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis 总被引:7,自引:2,他引:7
Li DY; Toland AE; Boak BB; Atkinson DL; Ensing GJ; Morris CA; Keating MT 《Human molecular genetics》1997,6(7):1021-1028
Supravalvular aortic stenosis (SVAS) is an inherited obstructive vascular
disease that affects the aorta, carotid, coronary and pulmonary arteries.
Previous molecular genetic data have led to the hypothesis that SVAS
results from mutations in the elastin gene, ELN. In these studies, the
disease phenotype was linked to gross DNA rearrangements (35 and 85 kb
deletions and a translocation) in three SVAS families. However, gross
rearrangements of ELN have not been identified in most cases of autosomal
dominant SVAS. To define the spectrum of ELN mutations responsible for this
disorder, we refined the genomic structure of human ELN and used this
information in mutational analyses. ELN point mutations co-segregate with
the disease in four familial cases and are associated with SVAS in three
sporadic cases. Two of the mutations are nonsense, one is a single base
pair deletion and four are splice site mutations. In one sporadic case, the
mutation arose de novo. These data demonstrate that point mutations of ELN
cause autosomal dominant SVAS.
相似文献
14.
15.
Usami S Takahashi K Yuge I Ohtsuka A Namba A Abe S Fransen E Patthy L Otting G Van Camp G 《European journal of human genetics : EJHG》2003,11(10):744-748
The COCH gene is the only gene identified in man that causes autosomal dominantly inherited hearing loss associated with vestibular dysfunction. The condition is rare and only five mutations have been reported worldwide. All affected families showed a similar progressive hearing loss and vestibular dysfunction. Since Meniere's disease-like symptoms have also been described in some families, it was suggested that COCH mutations might be present in some patients diagnosed with Meniere's disease. In this study, using a Japanese population, we performed a COCH mutation analysis in 23 patients from independent families with autosomal dominant hearing impairment, four of whom reported vestibular symptoms, and also in 20 Meniere's patients. While a new point mutation, A119 T, was found in a patient with autosomal dominant hearing loss and vestibular symptoms, no mutations were found in the Meniere's patients. Like all other previously identified COCH mutations, the mutation identified here is a missense mutation located in the FCH domain of the protein. The current mutation is located in close spatial proximity to W117, in which a mutation (W117R) had previously been associated with autosomal dominant hearing loss. Model building suggests that, like the W117R mutation, the A119 T mutation does not affect the structural integrity of the FCH domain, but may interfere with the interaction with a yet unknown binding partner. We conclude that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominantly inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction, or sporadic Meniere's disease. 相似文献
16.
Schollen E Matthijs G Gewillig M Fryns JP Legius E 《European journal of human genetics : EJHG》2003,11(1):85-88
Noonan syndrome (NS, MIM 163950) is an autosomal dominant condition characterised by facial dysmorphy, congenital cardiac defects and short stature. Recently missense mutations in PTPN11, the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2 on 12q24, were identified in 50% of analysed Noonan cases. A large four-generation Belgian family with NS and some features suggestive of cardio-facio-cutaneous syndrome (CFC) was previously used to fine map the Noonan syndrome candidate region to a 5 cM region in 12q24. We now report the identification of a mutation (Gln79Arg) in the PTPN11 gene in this large family. In D. melanogaster and C. elegans the PTPN11 gene has been implicated in oogenesis. In this family two affected females had dizygous twins. This suggests that PTPN11 might also be involved in oogenesis and twinning in humans. 相似文献
17.
An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection 总被引:2,自引:0,他引:2
Watnick TJ; Piontek KB; Cordal TM; Weber H; Gandolph MA; Qian F; Lens XM; Neumann HP; Germino GG 《Human molecular genetics》1997,6(9):1473-1481
The gene for the most common and severe form of autosomal dominant
polycystic kidney disease, PKD1, encodes a 14 kb mRNA that is predicted to
result in an integral membrane protein of 4302 amino acids. The major
challenge faced by researchers attempting to complete mutation analysis of
the PKD1 gene has been the presence of several homologous loci also located
on chromosome 16. Because the sequence of PKD1 and its homologs is nearly
identical in the 5' region of the gene, most traditional approaches to
mutation analysis cannot distinguish sequence variants occurring uniquely
in PKD1. Therefore, only a small number of mutations have been identified
to date and these have all been found in the 3', unique portion of the
gene. In order to begin analysis of the duplicated region of PKD1, we have
devised a novel strategy that depends on long-range PCR and a single
gene-specific primer from the unique region of the gene to amplify a
PKD1-specific template that spans exons 23-34. This 10 kb template,
amplified from genomic DNA, can be employed for mutation analysis using a
wide variety of sequence- based approaches. We have used our long-range PCR
strategy to begin screening for sequence variants with heteroduplex
analysis, and several affected individuals were discovered to have clusters
of base pair substitutions in exons 23 and 25. In two patients, these
changes, identified in exon 23, would be predicted to result in multiple
amino acid substitutions in a short stretch of the protein. This clustering
of base pair substitutions is unusual and suggests that mutation may result
from unique structural features of the PKD1 gene.
相似文献
18.
Baris O Delettre C Amati-Bonneau P Surget MO Charlin JF Catier A Derieux L Guyomard JL Dollfus H Jonveaux P Ayuso C Maumenee I Lorenz B Mohammed S Tourmen Y Bonneau D Malthièry Y Hamel C Reynier P 《Human mutation》2003,21(6):656-656
The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy. 相似文献
19.
20.
Paul G Horan Adrian R Allen Anne E Hughes Chris C Patterson Mark Spence Paul G McGlinchey Christine Belton Tracy CL Jardine Pascal P McKeown 《BMC medical genetics》2006,7(1):65-4