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1.
Shastry BS Hejtmancik FJ Trese MT 《Biochemical and biophysical research communications》1999,256(2):317-319
Congenital retinoschisis (RS) is a hereditary eye disorder characterized by intraretinal schisis and central and peripheral retinal lesion. The gene responsible for the X-linked retinoschisis (XLRS1) has recently been isolated and found to contain mutations in affected members of several families. In this communication, two families with X-linked RS were analyzed for possible disease-causing mutations by polymerase chain reaction amplification of exons followed by DNA sequencing. Our analyses reveal a missense mutation at codon 197 in exon 6 and a nonsense mutation in exon-4 of XLRS1 gene. These changes resulted in the replacement of a highly conserved arginine by a cysteine residue and introduced a premature termination signal at codon 89, respectively. These mutations, which are transmitted through three generations, cosegregated with the disease, and are not found in the unaffected family members and 150 normal X-chromosomes, are likely to be pathogenic in these families. 相似文献
2.
Gerard D. Schellenberg Leojean Anderson Sheldon O''''dahl Ellen M. Wisjman Adele D. Sadovnick Melvyn J. Ball Eric B. Larson Walter A. Kukull George M. Martin Allen D. Roses Thomas D. Bird 《American journal of human genetics》1991,49(3):511-517
The amyloid precursor protein (APP) gene codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 "sporadic" AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis-Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD. 相似文献
3.
Y. Hotta Keiko Fujiki Mutsuko Hayakawa Takashi Ohta Takuro Fujimaki Kouichi Tamaki Toshiyuki Yokoyama Atsushi Kanai Akito Hirakata Tetsuo Hida Sachiko Nishina Noriyuki Azuma 《Human genetics》1998,103(2):142-144
We investigated the XLRS1 gene in Japanese patients with retinoschisis (RS). All exons of the XLRS1 gene were sequenced in 14 males, including a pair of monozygotic twins, from 11 individual families with RS and five of their
mothers who are asymptomatic but diagnosed as carriers. Six kinds of missense mutations and a nonsense mutation, including
six novel mutations, were detected in all 14 patients and carriers. Mutations in the XLRS1 gene are also responsible for RS in non-Caucasian patients. Most Japanese RS cases are caused by an XLRS1 gene defect. A novel mutation, Glu72Lys, was found in four families, suggesting a common mutation in the Japanese population.
Clinical features of RS patients with both the Glu72Lys and Pro193Leu mutations indicate that a genotype–phenotype correlation
is not recognized in RS.
Received: 12 January 1998 / Accepted: 21 March 1998 相似文献
4.
C. Walon Alex Kartheuser Geneviève Michils Michèle Smaers Nathalie Lannoy Patrick Ngounou G. Mertens Christine Verellen-Dumoulin 《Human genetics》1997,100(5-6):601-605
Among 23 germline mutations identified in the APC screening of 45 familial adenomatous polyposis (FAP) patients, we have found 10 different novel frameshift mutations in 11
apparently unrelated patients. In two cases, an additional missense mutation was detected. One previously described as a causative
germline mutation (S2621C), associated with a 1-bp insertion (4684insA) on the opposite allele, did not segregate with the
FAP phenotype in the family and was therefore considered as being non-pathogenic. The other (Z1625H) was located 2 codons
before a 1-bp deletion (4897delC). Both mutations were transmitted together from an FAP father to his affected son. The FAP
phenotype of these 10 novel truncating mutations was clinically documented within their kindreds. Important variability was
observed in the phenotype. Interestingly, we noted that a mutation (487insT) localized at the boundary of the 5’ attenuated
APC phenotype region in two unrelated families resulted in classical polyposis. A clear-cut genotype-phenotype correlation
could be drawn in only two instances. In one family, a 4684insA mutation led to a mild polyposis associated with early inherited
osteomas and, in the family bearing the double mutation (Z1625H+4897delC), the phenotype was obviously a 3′ attenuated type.
Our data illustrate the wide genetic and phenotypic heterogeneity of this condition between and within the families, making
the establishment of correlations complex and any prediction in this disease difficult, although targeting the mutation site
may be helpful in some specific cases.
Received: 11 February 1997 / Accepted: 11 April 1997 相似文献
5.
Identification and expression of mutations in the hydroxymethylbilane synthase gene causing acute intermittent porphyria (AIP) 下载免费PDF全文
Solis C Lopez-Echaniz I Sefarty-Graneda D Astrin KH Desnick RJ 《Molecular medicine (Cambridge, Mass.)》1999,5(10):664-671
BACKGROUND: Acute intermittent porphyria (AIP), an autosomal dominant inborn error, results from the half-normal activity of the heme biosynthetic enzyme hydroxymethylbilane synthase (EC 4.3.1.8; HMB-synthase). This disease is characterized by acute, life-threatening neurologic attacks that are precipitated by various drugs, hormones, and other factors. The enzymatic and/or biochemical diagnosis of AIP heterozygotes is problematic; therefore, efforts have focused on the identification of HMB-synthase mutations so that heterozygotes can be identified and educated to avoid the precipitating factors. In Spain, the occurrence of AIP has been reported, but the nature of the HMB-synthase mutations causing AIP in Spanish families has not been investigated. Molecular analysis was therefore undertaken in nine unrelated Spanish AIP patients. MATERIALS AND METHODS: Genomic DNA was isolated from affected probands and family members of nine unrelated Spanish families with AIP. The HMB-synthase gene was amplified by long-range PCR and the nucleotide sequence of each exon was determined by cycle sequencing. RESULTS: Three new mutations, a missense, M212V; a single base insertion, g4715insT; and a deletion/insertion, g7902ACT-->G, as well as five previously reported mutations (G111R, R116W, R149X R167W, and R173W) were detected in the Spanish probands. Expression of the novel missense mutation M212V in E. coli revealed that the mutation was causative, having <2% residual activity. CONCLUSIONS: These studies identified the first mutations in the HMB-synthase gene causing AIP in Spanish patients. Three of the mutations were novel, while five previously reported lesions were found in six Spanish families. These findings enable accurate identification and counseling of presymptomatic carriers in these nine unrelated Spanish AIP families and further demonstrate the genetic heterogeneity of mutations causing AIP. 相似文献
6.
Malignant hyperthermia (MH) and central core disease (CCD) are two conditions associated with susceptibility to volatile anesthetics and depolarizing muscle relaxants. The gene RYR1, encoding the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum, is responsible for about 50% of the cases of MH and some cases of CCD. However, genetic heterogeneity occurs in MH and a mutation in a second gene (CACLN1A3), encoding the alpha1-subunit of the dihydropyridine (DHP) channel, has recently been found in a large MH French family. The presence of this mutation in patients with CCD has not yet been reported. In this study, we analyzed the A3333G mutation in 5 unrelated patients affected by CCD and 31 MH-susceptible relatives (from 19 MH families) and did not find this mutation in any of them. Nevertheless, the report of data on newly described mutations in different populations is important to estimate the contributions of each gene mutation to the phenotype of MH and CCD. 相似文献
7.
Puig JG Prior C Martínez-Ara J Torres RJ 《Nucleosides, nucleotides & nucleic acids》2006,25(9-11):1295-1300
Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency. 相似文献
8.
J. G. Puig C. Prior J. Martínez-Ara R. J. Torres 《Nucleosides, nucleotides & nucleic acids》2013,32(9-11):1295-1300
Since 1993 we have studied 5 Spanish families with familial nephropathy associated with hyperuricemia (FJHN). Among these families, 24 patients have been identified. All patients had some combination of hyperuricemia, gout, renal insufficiency, arterial hypertension, and reduced kidney size. The clinical presentation in the different families and in the members of the same family was heterogeneous. Allopurinol treatment did not appear to influence renal disease. From a clinical perspective, this syndrome is a distinctive interstitial nephropathy, inherited as an autosomal dominant trait, that progresses to renal failure and is not halted nor prevented by allopurinol therapy. In 2003, genetic linkage analysis in 3 of the 5 families showed linkage of FJHN to 16p 11.2. One family was not analyzed and one family did not show linkage to this region confirming the genetic heterogeneity of this syndrome. A mutation in UMOD gene was found in these 3 families as the cause of the FJHN. The mutations cluster in exon 4 and exon 5 and were point mutation that results in an amino acid change in the uromodulin or Tamm Horsfall protein. This fact allowed in 2004, the presymptomatic genetic diagnosis of an 8-years-old boy belonging to one of these 3 Spanish families. We conclude that in families with a history of renal failure and/or gout in which FJHN is suspected, UMOD mutation screening may enable a definite diagnosis. When a mutation is found, family members can be tested for a UMOD mutation and pre-symptomatic diagnosis may allow counseling to prevent or halt the progression to renal insufficiency. 相似文献
9.
Juan Dong Jenny Chang-Claude Yixin Wu Valérie Schumacher Irmgard Debatin Patricia Tonin Brigitte Royer-Pokora 《Human genetics》1998,103(2):154-161
We have analyzed 61 German breast and breast/ovarian cancer families for BRCA1 mutations using single-strand conformation
polymorphism analysis (SSCP) followed by sequencing. Forty-seven of the families had at least three cases (at least two under
60 years) and 14 families had only two cases of breast/ovarian cancer (at least one under 50 years). Twenty-eight families
were breast/ovarian and 33 were breast cancer-only families. Eighteen mutations in BRCA1 were detected in 11/28 breast/ovarian
cancer families and 7/33 breast cancer families and none in the families with only two cases. We identified 17 truncation
mutations (8 frameshift, 7 nonsense and 2 splice variants) and one missense mutation. Seven of these are novel and two, the
5382insC and 5622C→T mutations, occurred in two apparently unrelated families. The genotype of the two families with the 5382insC
mutation is compatible with the rare haplotype segregating with the 5382insC mutation in different populations, further supporting
its European origin. One unclassified missense alteration, R841W, was found in one family but did not segregate with the disease,
suggesting that it is more likely a polymorphism. We also report and discuss the sequence of several new unclassified single-nucleotide
changes first identified by SSCP. Of the 18 mutations, 13 occurred in the 3′ third of the gene (end of exon 11–24) and ovarian
cancers were found in eight of these families.
Received: 5 February 1998 / Accepted: 7 April 1998 相似文献
10.
Alpana Dave Kate Laurie Sandra E. Staffieri Deepa Taranath David A. Mackey Paul Mitchell Jie Jin Wang Jamie E. Craig Kathryn P. Burdon Shiwani Sharma 《PloS one》2013,8(8)
Congenital cataract is the most common cause of treatable visual impairment in children worldwide. Mutations in many different genes lead to congenital cataract. Recently, mutations in the receptor tyrosine kinase gene, EPHA2, have been found to cause congenital cataract in six different families. Although these findings have established EPHA2 as a causative gene, the total contribution of mutations in this gene to congenital cataract is unknown. In this study, for the first time, a population-based approach was used to investigate the frequency of disease causing mutations in the EPHA2 gene in inherited cataract cases in South-Eastern Australia. A cohort of 84 familial congenital or juvenile cataract index cases was screened for mutations in the EPHA2 gene by direct sequencing. Novel changes were assessed for segregation with the disease within the family and in unrelated controls. Microsatellite marker analysis was performed to establish any relationship between families carrying the same mutation. We report a novel congenital cataract causing mutation c.1751C>T in the EPHA2 gene and the previously reported splice mutation c.2826-9G>A in two new families. Additionally, we report a rare variant rs139787163 potentially associated with increased susceptibility to cataract. Thus mutations in EPHA2 account for 4.7% of inherited cataract cases in South-Eastern Australia. Interestingly, the identified rare variant provides a link between congenital and age-related cataract. 相似文献
11.
Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene 总被引:3,自引:0,他引:3
Gallione CJ Scheessele EA Reinhardt D Duits AJ Berg JN Westermann CJ Marchuk DA 《Human genetics》2000,107(1):40-44
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant bleeding disorder characterized by localized angiodysplasia. Mutations in either of two genes, endoglin or ALK-1, can cause HHT. Both genes encode putative receptors for the transforming growth factor-beta superfamily of ligands. Many mutations in each gene have been identified in HHT kindreds from around the world, and with few exceptions mutations are unique and family specific. The prevalence of HHT in the Leeward Islands of the Netherlands Antilles is possibly the highest of any geographical location. We wished to establish whether this high prevalence is due to a genetic founder effect or to multiple mutational events. HHT kindreds from the Netherlands Antilles and The Netherlands were screened for mutations in the two genes associated with HHT. Haplotype analysis of a 5-cM region on chromosome 9 flanking the endoglin gene revealed three distinct disease haplotypes in the ten Antillean families studied. Seven of these families share a splice-site mutation in exon 1 of endoglin. Two other Antillean families share a missense mutation in exon 9a of endoglin. This mutation was also found in a Dutch family that shares the same disease haplotype as the Antillean families with this mutation. Thus it appears that HHT in the Netherlands Antilles is due to a limited number of ancestral mutations in the endoglin gene, and that one of these mutations was introduced into the African slave population by a Dutch colonist. The limited scope of mutations suggests that a presymptomatic screening program for HHT would be feasible in this population. 相似文献
12.
Ataxia with isolated vitamin E deficiency: heterogeneity of mutations and phenotypic variability in a large number of families. 总被引:13,自引:0,他引:13
L Cavalier K Ouahchi H J Kayden S Di Donato L Reutenauer J L Mandel M Koenig 《American journal of human genetics》1998,62(2):301-310
Ataxia with vitamin E deficiency (AVED), or familial isolated vitamin E deficiency, is a rare autosomal recessive neurodegenerative disease characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. We recently have demonstrated that AVED is caused by mutations in the gene for alpha-tocopherol transfer protein (alpha-TTP). We now have identified a total of 13 mutations in 27 families. Four mutations were found in >=2 independent families: 744delA, which is the major mutation in North Africa, and 513insTT, 486delT, and R134X, in families of European origin. Compilation of the clinical records of 43 patients with documented mutation in the alpha-TTP gene revealed differences from Friedreich ataxia: cardiomyopathy was found in only 19% of cases, whereas head titubation was found in 28% of cases and dystonia in an additional 13%. This study represents the largest group of patients and mutations reported for this often misdiagnosed disease and points to the need for an early differential diagnosis with Friedreich ataxia, in order to initiate therapeutic and prophylactic vitamin E supplementation before irreversible damage develops. 相似文献
13.
Genetic heterogeneity in Leber hereditary optic neuroretinopathy revealed by mitochondrial DNA polymorphism. 总被引:5,自引:10,他引:5 下载免费PDF全文
The presence or absence of a recently observed mitochondrial DNA (mtDNA) mutation associated with Leber hereditary optic neuroretinopathy (LHON) was tested in 19 Finnish families with cases of LHON. Leukocyte and muscle DNA from individuals with optic atrophy, microangiopathy, or normal fundi from maternal lineages were studied by Southern blot analysis, using mouse mtDNA as a hybridization probe. The mtDNA mutation, detected as SfaNI site polymorphism, was seen in 10 of the 19 families. In one family, the mutation was seen only in the two affected individuals, indicating recent origin for the mutation. Nine families and 28 maternally unrelated controls did not show the mutation. The results imply that alternative mtDNA mutations are associated with LHON and that this genetic heterogeneity may be the cause of the interfamilial variation in the clinical expression of LHON. In the families showing the SfaNI site mutation, the mutation was homoplasmic in all individuals irrespective of their disease status, suggesting that the intrafamilial variation in the clinical expression is not due to different ratios of mutant versus normal mtDNA. 相似文献
14.
Halling KC Lazzaro CR Honchel R Bufill JA Powell SM Arndt CA Lindor NM 《Human heredity》1999,49(2):97-102
Two families with autosomal dominantly inherited desmoid tumors have recently been shown to have germline mutations at the 3' end of the APC gene. We subsequently identified an Amish family with autosomal dominantly inherited desmoid tumors. Genetic analysis performed on one family member, a 47-year-old man with multiple desmoid tumors and no colon polyps, revealed a protein truncating mutation in the middle of the APC gene. The truncating mutation is the result of a 337-bp insertion of an Alu I sequence into codon 1526 of the APC gene. The presence of a poly(A) tail at the 3' end of the insertion suggests that the Alu I sequence was inserted by a retrotranspositional event. Germline insertions of Alu I sequences have occasionally been reported to cause other genetic diseases including type I neurofibromatosis, hereditary site-specific breast cancer (BRCA2), and hemophilia B. However, this is the first report of a germline mutation of the APC gene resulting from an Alu I insertion. 相似文献
15.
Meléndez B Rodríguez-Perales S Martínez-Delgado B Otero I Robledo M Martínez-Ramírez A Ruiz-Llorente S Urioste M Cigudosa JC Benítez J 《Human genetics》2003,112(2):178-185
An alternative model has been proposed for the development of clear-cell renal cell carcinoma (RCC) in families where chromosome 3 translocations segregate with the disease. In this model, the existence of a translocation involving chromosome 3 would favour the non-disjunctional loss of the derivative chromosome carrying the 3p segment. Additionally, subsequent somatic mutations in the VLH gene, located in 3p25-26, would inactivate this tumour suppressor gene. In the present work, we describe a new family with two clear-cell RCC affected members and a t(3;8)(p13;q24.1) translocation in two consecutive generations. We observed loss of the derivative chromosome carrying the 3p segment (der(8)) and somatic mutation of the VHL gene in the left-kidney tumoral tissue of the proband. His right-kidney tumour carried a different VHL mutation and loss of heterozygosity (LOH) was not detected. The mother of the proband was also clear-cell RCC-affected but the tumoral tissue analysed did not carry any VHL gene mutations. Another member of the family, a maternal aunt, had a papillary RCC and did not carry this translocation, the LOH on 3p or the VHL somatic mutations. Haplotype analysis of the three affected members revealed that they did not inherit a common region on 3p, confirming the different genetic origin of both tumour types. Finally, the presence of RCC in other non-available members of the family highlights the overall risk for RCC in families with chromosome 3 translocations. In the present work, we have confirmed the proposed mechanism for the development of clear-cell RCC in this family, although we cannot discard the existence of other genes, in addition to VHL, being involved in hereditary RCC. 相似文献
16.
Crisponi syndrome is caused by mutations in the CRLF1 gene and is allelic to cold-induced sweating syndrome type 1 下载免费PDF全文
Crisponi L Crisponi G Meloni A Toliat MR Nurnberg G Usala G Uda M Masala M Hohne W Becker C Marongiu M Chiappe F Kleta R Rauch A Wollnik B Strasser F Reese T Jakobs C Kurlemann G Cao A Nurnberg P Rutsch F 《American journal of human genetics》2007,80(5):971-981
Crisponi syndrome is a severe autosomal recessive condition that is phenotypically characterized by abnormal, paroxysmal muscular contractions resembling neonatal tetanus, large face, broad nose, anteverted nares, camptodactyly, hyperthermia, and sudden death in most cases. We performed homozygosity mapping in five Sardinian and three Turkish families with Crisponi syndrome, using high-density single-nucleotide polymorphism arrays, and identified a critical region on chromosome 19p12-13.1. The most prominent candidate gene was CRLF1, recently found to be involved in the pathogenesis of cold-induced sweating syndrome type 1 (CISS1). CISS1 belongs to a group of conditions with overlapping phenotypes, also including cold-induced sweating syndrome type 2 and Stuve-Wiedemann syndrome. All these syndromes are caused by mutations of genes of the ciliary neurotrophic factor (CNTF)-receptor pathway. Here, we describe the identification of four different CRLF1 mutations in eight different Crisponi-affected families, including a missense mutation, a single-nucleotide insertion, and a nonsense and an insertion/deletion (indel) mutation, all segregating with the disease trait in the families. Comparison of the mutation spectra of Crisponi syndrome and CISS1 suggests that neither the type nor the location of the CRLF1 mutations points to a phenotype/genotype correlation that would account for the most severe phenotype in Crisponi syndrome. Other, still-unknown molecular factors may be responsible for the variable phenotypic expression of the CRLF1 mutations. We suggest that the syndromes can comprise a family of "CNTF-receptor-related disorders," of which Crisponi syndrome would be the newest member and allelic to CISS1. 相似文献
17.
Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases 下载免费PDF全文
Rudolph E. Tanzi Giovanna Vaula Donna M. Romano Marzia Mortilla Tricia L. Huang Rossella G. Tupler Wilma Wasco Bradley T. Hyman Jonathan L. Haines Barbara J. Jenkins Marianna Kalaitsidaki Andrew C. Warren Melvin C. McInnis Stylianos E. Antonarakis Harry Karlinsky Maire E. Percy Linda Connor John Growdon Donald R. Crapper-McIachlan James F. Gusella Peter H. St George-Hyslop 《American journal of human genetics》1992,51(2):273-282
A genetic locus associated with familial Alzheimer disease (FAD) and a candidate gene, APP, encoding the amyloid protein precursor have both been assigned previously to chromosome 21, and, in a few FAD families, mutations of APP have been detected. However, obligate crossovers between APP and FAD have also been reported in several FAD pedigrees, including FAD4, a large kindred showing highly suggestive evidence for linkage of the disorder to chromosome 21. In case the apparent APP crossover in FAD4 actually represented an intragenic recombination event or segregation of different mutations in different family branches, we have performed a more detailed assessment of APP as a candidate gene in this family. The entire coding region of the APP gene was sequenced for FAD4 and for FAD1, a second large kindred. No mutations were found, indicating that, in at least one chromosome 21-linked FAD pedigree, the gene defect is not accounted for by a mutation in the known coding region of the APP gene. A total of 25 well-characterized early- and late-onset FAD pedigrees were typed for genetic linkage to APP, to assess the percentage of FAD families predicted to carry mutations in the APP gene. None of the FAD families yielded positive lod scores at a recombination fraction of 0.0. To estimate the overall prevalence of FAD-associated mutations in the beta A4 domain of APP, we sequenced exons 16 and 17 in 30 (20 early- and 10 late-onset) FAD kindreds and in 11 sporadic AD cases, and we screened 56 FAD kindreds and 81 cases of sporadic AD for the presence of the originally reported FAD-associated mutation, APP717 Val----Ile (by BclI digestion). No APP gene mutations were found in any of the FAD families or sporadic-AD samples examined in this study, suggesting that the mutations in exons 16 and 17 are a rare cause of FAD. Overall, these data suggest that APP gene mutations account for a very small portion of FAD. 相似文献
18.
The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy 总被引:13,自引:0,他引:13
Kirsi Huoponen Tarja Lamminen Vesa Juvonen Pertti Aula Eeva Nikoskelainen Marja -Liisa Savontaus 《Human genetics》1993,92(4):379-384
The mitochondrial complex I genes were sequenced in seven Leber hereditary optic neuroretinopathy (LHON) families without the ND4/11778 and ND1/3460 mutations. Four replacement mutations restricted only to LHON families were found, one in the ND1 gene at nt 4025, and three in the ND5 gene at nt 12811, 13637, and 13967. The mutations did not change evolutionarily conserved amino acids suggesting that they are not primary LHON mutations in these families. They may be considered as secondary LHON mutations serving as exacerbating factors in an appropriate genetic background. A complex III mutation, cyt b/15257, has been suggested to be one of the primary mutations causing LHON. Its presence was determined for 23 Finnish LHON families, and it was detected in two families harboring the ND4/11778 mutation. Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation. 相似文献
19.
Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome 下载免费PDF全文
Schmidt LS Nickerson ML Warren MB Glenn GM Toro JR Merino MJ Turner ML Choyke PL Sharma N Peterson J Morrison P Maher ER Walther MM Zbar B Linehan WM 《American journal of human genetics》2005,76(6):1023-1033
Birt-Hogg-Dubé syndrome (BHD), a genodermatosis characterized by multiple hamartomas of the hair follicle (fibrofolliculoma), predisposes individuals to an increased risk of developing renal neoplasms and spontaneous pneumothorax. Previously, we localized the BHD locus (also known as FLCN) to chromosome 17p11.2 by linkage analysis and subsequently identified germline mutations in a novel gene in probands from eight of the nine families with BHD in our screening panel. Affected members of five of the families inherited an insertion/deletion of a cytosine in a C8 tract in exon 11. This mutation was also identified by exon 11 screening in probands from 22 of 52 additional families with BHD and therefore represents a hypermutable "hotspot" for mutation in BHD. Here, we screened the remaining 30 families from this large BHD cohort by direct sequence analysis and identified germline BHD mutations in 84% (51/61) of all families with BHD recruited to our study. Mutations were located along the entire length of the coding region, including 16 insertion/deletion, 3 nonsense, and 3 splice-site mutations. The majority of BHD mutations were predicted to truncate the BHD protein, folliculin. Among patients with a mutation in the exon 11 hotspot, significantly fewer renal tumors were observed in patients with the C-deletion than those with the C-insertion mutation. Coding-sequence mutations were not found, however, in probands from two large families with BHD whose affected members shared their family's BHD-affected haplotype. Of the 53 families with BHD whose members inherited either a germline mutation or the affected haplotype, 24 (45%) had at least one member with renal neoplasms. Three families classified with familial renal oncocytoma were identified with BHD mutations, which represents the first disease gene associated with this rare form of renal neoplasm. This study expands the BHD-mutation spectrum and evaluates genotype-phenotype correlations among families with BHD. 相似文献
20.
Górski B Debniak T Jakubowska A Cybulski C Huzarski T Byrski T Złowocka E Lubiński J 《Journal of applied genetics》2003,44(3):419-423
Founder mutations can account for a large proportion of BRCA1/BRCA2 gene abnormalities in a given population. However there is still a need to study the entire gene in many families, even in countries where founder mutations have been identified. It is possible to decrease the number of cases which are studied by complex and expensive sequencing/Southern blot analyses of BRCA1/BRCA2 genes by exclusion of common BRCA1/BRCA2 alleles in a given family by using polymorphic dinucleotide markers. The goal of o ur study was to assess the effectiveness of this method in exclusion of BRCA1/BRCA2 constitutional mutations. In each family, blood samples for genetic analyses were taken from two affected relatives from the same generation. Six polymorphic microsatellite markers linked to BRCA1/BRCA2 genes were analysed. Results obtained with these markers were verified by applying BRCA1 testing for the most common founder mutations in Poland and using exon by exon" sequencing of coding fragments of the BRCA2 gene. Polymorphic markers useful in BRCA1/BRCA2 analyses included only 3 of 6 examined - D17S855, D13S260 and D13S267. Occurrence of commoalleles of BRCA1 was excluded in 3 families and BRCA2 in 5 out of 30 families. Results obtained by testing for BRCA1 Polish founder mutations and BRCA2 sequencing were in agreement with BRCA1 findings based on polymorphic markers. The only exception was family 994 with BRCA1 exon 5 300T/G mutation, in which BRCA1 mutation carrier was excluded by using D17S855. Among 14 families without BRCA1 Polish founder mutations in this gene were excluded in 2 families and BRCA2 mutation was excluded in one family. 相似文献