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1.
Makaoto Goto Osamu Imamura Junro Kuromitsu Takehisa Matsumoto Yukako Yamabe Yoshiki Tokutake Noriyuki Suzuki Brian Mason Dennis Drayna Minoru Sugawara Masanobu Sugimoto Y. Furuichi 《Human genetics》1997,99(2):191-193
The profile of helicase gene mutations was studied in 89 Japanese Werner’s syndrome (WRN) patients by examining the previously
described mutations 1– 4 as well as a new mutation found during this study, designated mutation 5. Of 178 chromosomes (89
patients), 89 chromosomes (50%) had mutation 4, 11 (6.2%) chromosomes had mutation 1, and two chromosomes (1.1%) contained
mutation 5. Mutations 2 and 3 were not observed in this patient population. The remaining 76 (42.7%) chromosomes had none
of these mutations. A significant fraction of all patients (22 total patients, 24.7%) appear to be compound heterozygotes,
including those carrying mutations of both types 1 and 4. The genotype analysis of the markers surrounding the WRN helicase gene strongly suggests that most of the chromosomes carrying either mutation 1 or 4 were derived from two single
founders.
Received: 25 July 1996 / Revised: 20 September 1996 相似文献
2.
G. E. Hollway Graeme K. Suthers Eric A. Haan Elizabeth Thompson David J. David Jozef Gecz John C. Mulley 《Human genetics》1997,99(2):251-255
Five autosomal dominant craniosynostosis syndromes (Apert, Crouzon, Pfeiffer, Jackson-Weiss and Crouzon syndrome with acanthosis
nigricans) result from mutations in FGFR genes. Fourteen unrelated patients with FGFR2-related craniosynostosis syndromes were screened for mutations in exons IIIa and IIIc of FGFR2. Eight of the nine mutations found have been reported, but one patient with Pfeiffer syndrome was found to have a novel G-to-C
splice site mutation at –1 relative to the start of exon IIIc. Of those mutations previously reported, the mutation C1205G
was unusual in that it was found in two related patients, one with clinical features of Pfeiffer syndrome and the other having
mild Crouzon syndrome. This degree of phenotypic variability shows that the clinical features associated with a specific mutation
do not necessarily breed true.
Received: 4 June 1996 / Revised: 3 September 1996 相似文献
3.
Dau-Ming Niu Kwang-Jen Hsiao Nai-Hwei Wang Lin-Show Chin C.-H. Chen 《Human genetics》1996,98(1):65-67
Achondroplasia is the most common form of dwarfism in humans. A recurrent glycine-to-arginine mutation at codon 380 (G380R)
of the transmembrane domain of fibroblast growth factor receptor-3 (FGFR-3) was identified in the majority of Western and
Japanese patients, which is uncommon in other autosomal dominant genetic diseases. To determine whether this mutation is also
common in Chinese patients, we examined the G380R mutation in Chinese patients with achondroplasia. Of ten patients studied,
including eight sporadic cases and one family with two affected members, all have the same G380R mutation with a G-to-A transition.
Our results support the argument that the G380R mutation of FGFR-3 is the most frequent mutation causing achondroplasia across
different populations.
Received: 8 January 1996 相似文献
4.
Antonio Rossi Hans J. van der Harten Frits A. Beemer Wim J. Kleijer Richard Gitzelmann Beat Steinmann A. Superti-Furga 《Human genetics》1996,98(6):657-661
Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias
that comprises, in order of increasing severity, diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis
type 1B (ACG1B). To learn more about the molecular basis of DTDST chondrodysplasias and about genotype-phenotype correlations,
we studied fibroblast cultures of three new patients: one with AO-2, one with DTD, and one with an intermediate phenotype
(AO2/DTD). Reduced incorporation of inorganic sulfate into macromolecules was found in all three. Each of the three patients
was found to be heterozygous for a c862t transition predicting a R279W substitution in the third extracellular loop of DTDST.
In two patients (DTD and AO2/DTD), no other structural mutation was found, but polymerase chain reaction amplification and
single-strand conformation polymorphism analysis of fibroblast cDNA showed reduced mRNA levels of the wild-type DTDST allele:
these two patients may be compound heterozygotes for the “Finnish” mutation (as yet uncharacterized at the DNA level), which
causes reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation,
the deletion of cytosine 418 (Δc418), predicting a frameshift with premature termination. Also the Δc418 allele was underrepresented
in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST
R279W mutation in a total of 11 patients with AO2 or DTD emphasizes the overlap between these conditions. This mutation has
not been found so far in 8 analyzed ACG1B patients, suggesting that it allows some residual activity of the sulfate transporter.
Received: 14 June 1996 / Revised: 8 August 1996 相似文献
5.
Direct DNA sequencing of the steroid 21-hydroxylase gene (CYP21) revealed two novel mutations in two patients with severe
congenital adrenal hyperplasia. The nonsense mutation Trp23Stop (TGG → TGA) was found in a woman with the simple virilizing
form of the disease. She was a compound heterozygote, with the previously described Ile173Asn mutation on her other allele.
A boy, who developed salt-wasting in the neonatal period, carried an allele with a novel mutation of the canonical splice
acceptor site in intron 1 (AG→GG). He was also a compound heterozygote, with the well-known splice mutation in intron 2 on
his other allele.
Received: 26 February 1996 相似文献
6.
D. M. Fathallah Mohamed Bejaoui Denis Lepaslier Khelifa Chater William S. Sly Koussay Dellagi 《Human genetics》1997,99(5):634-637
A splice junction mutation at the exon 2 – intron 2 boundary of the carbonic anhydrase II (CA II) gene was previously shown
to be the unique mutation underlying the CA II deficiency syndrome in patients of Arab descent. Fourteen Tunisian (Maghrebian)
families with a history of osteopetrosis, renal tubular acidosis, mental retardation, and CA II deficiency were studied to
test the hypothesis that the mutation, found in all 24 patients, derived from a common ancestor originating in the Arabic
Peninsula. A filiation study permitted us to trace these families back to a common Arabic tribe that settled in the Maghreb
in the tenth century, indicating a common ethnic origin for these families. Segregation of the mutation with a TaqI biallelic restriction site polymorphism upstream of the CA II gene was studied by sequence-tagged site analysis in all the
family members. These studies showed cosegregation of the Taq (-) allele with the mutation in 12 families out of 14. This observation supports a founder effect to explain the common CA
II deficiency allele in this population. In the remaining two families, a genomic recombination or gene conversion occurred
between the TaqI restriction marker and the mutation causing the disease. The relatively high recombination frequency suggests the presence
of a hot spot for recombination or gene conversion at the CA II locus.
Received: 5 July 1996 / Revised: 25 October 1996 相似文献
7.
M. Daimon Eishirou Gojyou Makoto Sugawara Keiichi Yamatani Makoto Tominaga Hideo Sasaki 《Human genetics》1997,99(2):199-201
Hereditary coproporphyria (HCP) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase.
To date, four mutations of the gene have been reported. We report here another mutation in two Japanese families with HCP,
which was revealed by analysis of polymerase chain reaction (PCR)-amplified DNA fragments of the gene by a direct-sequencing
method. A point mutation, G to A, was found in exon 4 of the gene at position 538 of the cDNA from the reported putative translation
initiation codon ATG. This mutation results in a glycine to arginine substitution at amino acid 180. Two carriers in the family
were successfully diagnosed by detecting the mutation using restriction analysis of the PCR products.
Received: 23 April 1996 / Revised: 15 July 1996 相似文献
8.
C. Ayuso María José Trujillo Mercedes Robledo Carmen Ramos Javier Benitez Félix Martín-Osés Teresa del Rio Blanca García-Sandoval 《Human genetics》1996,98(1):51-54
A family affected with autosomal dominant retinitis pigmentosa (RP) is presented. Two clinically affected patients (mother
and daughter) were heterozygous for the same novel missense mutation (Val137Met) of the rhodopsin gene (RHO). Both heterozygous
and homozygous cases were observed among their few symptomatic relatives. Wide clinical variation was exhibited among the
individuals with mutations in this family. None of the controls showed this change in RHO, nor has it been previously reported
in other RP families. No other RHO mutation was observed. Additional genetic or environmental factors could play a role in
modulating the penetrance and clinical expression of this RHO mutation.
Received: 20 February 1995 / Revised: 1 September 1995, 27 November 1995, 3 February 1996 相似文献
9.
Neurofibromatosis 2 (NF2) is a clinically variable autosomal dominant disorder, caused by mutations in the NF2 tumor suppressor gene on chromosome 22q12, that predisposes to nervous system tumors and ocular abnormalities. To assess intrafamilial
phenotypic variability, we performed mutation analysis and clinical assessment on two multigeneration NF2 families with five
patients and seven asymptomatic first-degree relatives of patients. One family had a point mutation of agCC→ggCC at position
1447–2 at the exon 13/14 boundary predicted to lead to an altered splice acceptor sequence and exon deletion. The other family
had an insertion of 2 base pairs (TC) at position 761 in exon 8, leading to a frameshift. Both mild and severe phenotypes
occurred in each family, indicating that phenotypic variability in NF2 can be caused by factors other than NF2 mutations. Genetic counseling of NF2 families should include the possibility that presymptomatic NF2 mutation carriers can develop a different phenotype than previously diagnosed patients.
Received: 4 January 1996 / Revised: 26 March 1996 相似文献
10.
X-linked congenital adrenal hypoplasia (AHC) is a developmental disorder of the human adrenal gland that results in profound
hormonal deficiencies, which are lethal if untreated. Hypogonadotropic hypogonadism (HHG) is frequently associated with this
disorder. The gene (DAX-1) responsible for the disease has recently been isolated. It encodes a protein with large similarity
to members of the nuclear hormone receptor superfamily. Several different mutations in this gene have been found in patients
suffering from AHC. We have identified a missense mutation (N440I) in three patients with AHC and HHG, all belonging to a
large Greenlandic family. A total of 42 individuals has been tested for this mutation. We have diagnosed 10 women as carriers,
and have excluded 22 women with a 25–50% risk from being carriers, emphasizing the rapid impact of molecular genetic techniques.
Received: 7 June 1996 / Revised: 5 August 1996 相似文献
11.
P. Carrera Laura Bordone Tiziana Azzani Valeria Brunelli Maria Paola Garancini Giuseppe Chiumello Maurizio Ferrari 《Human genetics》1996,98(6):662-665
Seventy-three Italian patients affected by steroid 21-hydroxylase deficiency were studied by a PCR –allele-specific oligonucleotide
protocol in order to evaluate the presence of eight known point mutations. The majority of chromosomes were found to carry
point gene conversions normally present in the pseudogene. Within the classic form, the most common mutations were the splicing
mutation A/C-655 to G in intron 2 (34.2%), the nonsense mutation C-1993 to T in exon 8 (10.8%), and the missense mutation
T-999 to A in exon 4 (10%). Within the non-classic form, the missense mutation G-1683 to T was the most common (57.7%). Other
mutations were either absent, such as the three clustered missense mutations T-1380, T-1383, T-1389 to A in exon 6, or very
rare, like the 1761 + T in exon 7 and the C-2108 to T in exon 8. Family genotyping revealed the presence of ten asymptomatic
parents carrying mutations in both chromosomes, thus identifying the gene defect in cryptic subjects. Interestingly, the same
mutations were found in both symptomatic and asymptomatic forms.
Received: 10 November 1995 / Revised: 18 March 1996, 30 May 1996 相似文献
12.
Hendrik G. de Vries M. A. van der Meulen Rima Rozen Dickie J. J. Halley Hans Scheffer Leo P. ten Kate Charles H. C. M. Buys G. J. te Meerman 《Human genetics》1996,98(3):304-309
Cystic fibrosis (CF) patients with the A455E mutation, in both the French Canadian and the Dutch population, share a common
haplotype over distances of up to 25 cM. French Canadian patients with the 621+1G→T mutation share a common haplotype of more
than 14 cM. In contrast, haplotypes containing the ΔF508 mutation show haplotype identity over a much shorter genomic distance
within and between populations, probably because of the multiple introduction of this most common mutation. Haplotype analysis
for specific mutations in CF or in other recessive diseases can be used as a model for studying the occurrence of genetic
drift conditional on gene frequencies. Moreover, from our results, it can be inferred that analysis of shared haplotypes is
a suitable method for genetic mapping in general.
Received: 30 November 1995 / Revised: 11 April 1996 相似文献
13.
K. Silander Päivi Meretoja Helena Pihko Vesa Juvonen Jouni Issakainen Pertti Aula Marja-Liisa Savontaus 《Human genetics》1997,100(3-4):391-397
The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is associated with mutations in a gene coding for the gap-junction
protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree pattern suggestive of X-linked inheritance for the
presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families had a CMT1 diagnosis, 24 had
a CMT2 diagnosis and 3 patients had an unspecified CMT. Eight families with a Cx32 point mutation were detected. Five different
mutations (four of them published previously) were found in six CMT2 families and one mutation was found in a sporadic CMT1
male patient. One of the mutations, Met194Val, is among the first described in the fourth transmembrane domain of Cx32. Two
CMT2 families and the sporadic CMT1 patient had the same mutation, Arg22Gln. An additional, previously unpublished mutation,
Arg75Trp, was found in a male patient with unspecified CMT, who subsequently was verified to have a variant Klinefelter syndrome
with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 patients, and
they emphasize the need for Cx32 mutation screening in families previously diagnosed with CMT2.
Received: 29 November 1996 / Revised: 17 February 1997 相似文献
14.
Robert J. Pomponio Karen J. Norrgard Jeanne Hymes Thomas R. Reynolds Gregory A. Buck Regula Baumgartner Terttu Suormala B. Wolf 《Human genetics》1997,99(4):506-512
Biotinidase deficiency is an autosomal recessively inherited disorder in the recycling of the vitamin biotin. The most common
mutation that causes profound biotinidase deficiency in symptomatic individuals is a deletion/insertion (G98:d7i3) that occurs in exon B of the biotinidase gene. We now report the second most common mutation, a C-to-T substitution
(position 1612) in a CpG dinucleotide in exon D of the biotinidase gene. This mutation results in the substitution of a cysteine
for arginine538 (designated R538C) and was found in 10 of 30 symptomatic children with profound biotinidase deficiency, 5
of whom also have the G98:d7i3 mutation. This mutation was not found in DNA samples from 32 individuals with normal biotinidase activity, but was found
in one individual with enzyme activity in the heterozygous range. This mutation was not detected in 371 randomly selected,
normal individuals using allele-specific oligonucleotide hybridization analysis. Aberrant biotinidase protein was not detectable
in extracts of fibroblasts from a child who is homozygous for the R538C mutation, but was present in less than normal concentration
in identical extracts treated with β-mercaptoethanol. Because there is no detectable biotinidase protein in sera of children
who are homozygous for the R538C mutation and in combination with the deletion/insertion mutation, the R538C mutation likely
results in inappropriate intra- or intermolecular disulfide bond formation, more rapid degradation of the aberrant enzyme,
and failure to secrete the residual aberrant enzyme from the cells into blood.
Received: 13 August 1996 / Revised: 13 November 1996 相似文献
15.
T. Kuramoto C. Sotelo N. Yokoi T. Serikawa E. Goñalons Sintes J. Cantó Martorell J. -L. Guénet 《Mammalian genome》1996,7(12):890-894
A recessive mutation exhibiting severe myelin breakdown, mainly at the level of the lumbar segments of the spinal cord and
without any associated inflammation, was discovered in a partially inbred rat colony. Analysis of the segregation patterns
of a set of polymorphic microsatellite markers in two inter-strain crosses allowed the mapping of this autosomal recessive
mutation to rat Chromosome (Chr) 17, very close to the prolactin (Prl) locus, in a region homologous to human Chr 6p21.2-22.3 and mouse Chr 13. The pathology of the demyelination process and
the chromosomal localization indicate that this mutation has no known equivalent in either mouse or human.
Received: 21 March 1996 / Accepted: 22 July 1996 相似文献
16.
Identification of WASP mutations,mutation hotspots and genotype-phenotype disparities in 24 patients with the Wiskott-Aldrich syndrome 总被引:2,自引:0,他引:2
Wenda L. Greer Amro Shehabeldin Jerry Schulman Anne Junker K. A. Siminovitch 《Human genetics》1996,98(6):685-690
The Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disease caused by mutation in the recently isolated gene
encoding WAS protein (WASP), is known to be associated with extensive clinical heterogeneity. Cumulative mutation data have
revealed that WASP genotypes are also highly variable among WAS patients, but the relationship of phenotype with genotype
in this disease remains unclear. To address this issue we characterized WASP mutations in 24 unrelated WAS patients, including
18 boys with severe classical WAS and 6 boys expressing mild forms of the disease, and then examined the degree of correlation
of these as well as all previously published WASP mutations with disease severity. By analysis of these compiled mutation
data, we demonstrated clustering of WASP mutations within the four most N-terminal exons of the gene and also identified several
sites within this region as hotspots for WASP mutation. These characteristics were observed, however, in both severe and mild
cases of the disease. Similarly, while the cumulative data revealed a predominance of missense mutations among the WASP gene
lesions observed in boys with isolated thrombocytopenia, missense mutations were not exclusively associated with milder WAS
phenotypes, but also comprised a substantial portion (38%) of the WASP gene defects found in patients with severe disease.
These findings, as well as the detection of identical WASP mutations in patients with disparate phenotypes, reveal a lack
of phenotype concordance with genotype in WAS and thus imply that phenotypic outcome in this disease cannot be reliably predicted
solely on the basis of WASP genotypes.
Received: 30 May 1996 / Revised: 16 July 1996 相似文献
17.
Deficiency of adenosine deaminase (ADA–) results in autosomal recessive immunodeficiency disease of varying severity. Partial ADA– [ADA deficiency in erythrocytes (RBCs) but substantial ADA in non-RBCs] has also been identified, primarily by population
screening of healthy adults in Africa and newborns in New York State. Normal immune function and/or minimal elevations of
toxic metabolites in childhood suggested that partial ADA deficiency was benign and therefore that six mutations identified
in partially ADA-deficient newborns and expressing 8–80% of normal ADA in non-RBCs were not pathogenic. However, the lowest
activity mutation (Arg211Cys) has now been reported in patients with adult-onset immunodeficiency. We have now molecularly
and biochemically studied two additional individuals whom we found to represent opposite ends of the spectrum of partial ADA
deficiency as to biochemical abnormalities and age of ascertainment. Homozygosity for a newly identified Leu152Met mutation
expressing considerably less activity than the pathogenic Arg211Cys mutation was found in a currently healthy 10-year-old
Afghanistani child (ascertained at birth). He had the highest accumulation of the metabolite dATP among 13 partially ADA-deficient
patients studied, but considerably lower than in those with immunodeficiency. Homozygosity for a newly identified Thr233Ile
mutation expressing somewhat greater ADA activity than Arg211Cys was found in a healthy young adult Kung individual, associated
with very low metabolite concentrations. Biochemical findings and a family history suggestive of immunodeficiency in prior
offspring support the idea that the Leu152Met mutation could result in disease in homozygous individuals challenged by severe
environmental insult or in heterozygosity with a null mutation. The pathogenicity of the Thr233Ile mutation, as well as a
previously described Ala215Thr mutation with relatively lower activity is less likely but will only be determined by long-term
observation of individuals carrying these mutations. Although, in contrast to other partial mutations, neither of these two
mutations are at CpG hot spots, the frequency of CpG mutations remains high for partial mutations but is also similarly high
in ADA– immunodeficient patients (5/8 vs 12/21).
Received: 7 August 1996 / Accepted: 29 November 1996 相似文献
18.
Nemat Hashem Paolo Bosco Valeria Chiavetta Francesco Calì Nadia Ceratto V. Romano 《Human genetics》1996,98(1):3-6
Mutation analysis at the phenylalanine hydroxylase (PAH) locus was undertaken in 56 Egyptian hyperphenylalaninemic patients.
Selected screening for 11 known mutations and denaturing Gradient gel electrophoresis (DGGE) analysis of the entire coding
sequence and exon/intron boundaries led to the identification of a new mutation (I224T), four previously described mutations,
and several polymorphisms. Overall, 18 mutant alleles could thus be characterized. In contrast to the high mutation detection
rate typical of the DGGE-based scanning approach, only 6 of 16 mutant alleles tested were identified. Since BH4 deficiency could not be excluded in any of these patients, the latter results may be explained by the occurrence of mutations
affecting the genes controlling the synthesis and recycling of tetrahydrobiopterin: the cofactor of PAH. An alternative hypothesis
is also discussed.
Received: 18 October 1995 / Revised: 30 January 1996 相似文献
19.
Alessandra Argiolas Paolo Bosco Francesco Calì Nadia Ceratto Guido Anello Enrica Riva Giacomo Biasucci Carla Carducci V. Romano 《Human genetics》1997,99(2):275-278
We report the identification by denaturing gradient gel electrophoresis and sequence analysis of two new phenylalanine hydroxylase
(PAH) gene mutations (IVS4nt-2 and N207S) in single chromosomes of two unrelated Italian phenylketonuric (PKU) patients. Interestingly,
mutation Y204C, found on the second mutant allele of family F1, has been previously detected in Chinese patients. Haplotype
analysis showed that the latter mutation is linked to the same haplotype (H4) in both Chinese and Italian patients, suggesting
a common origin. In vivo assessment of mutation severity indicates that N207S is associated with classic PKU. The identification
of these two new mutations further extends the remarkable heterogeneity of the PAH locus in the Italian population.
Received: 23 May 1996 相似文献
20.
A. Verrips Gerry C. H. Steenbergen-Spanjers J. A. F. M. Luyten L. P. W. J. van den Heuvel Antoine Keyser Fons J. M. Gabreëls Ron A. Wevers 《Human genetics》1996,98(6):735-737
This report concerns two new mutations in the sterol 27-hydroxylase gene in two patients with cerebrotendinous xanthomatosis
(CTX). In a Surinam-Creole patient (patient A), a G deletion on position cDNA 546/547 in exon 3 led to a frameshift and the
introduction of a premature termination codon. In a Dutch patient (patient B), a C→T transition at position 496 in exon 3
also led to a premature termination codon. Patient A was homozygous for the mutation, whereas patient B was compound heterozygous,
a C→T transition also being found in exon 6 at position 1204. The two new mutations were confirmed by restriction analysis
with the restriction enzymes FokI and MaeI, respectively.
Received: 24 July 1996 / Revised: 9 August 1996 相似文献