共查询到20条相似文献,搜索用时 15 毫秒
1.
F. R. Vargas E. Roessler Karin Gaudenz E. Belloni Alexander S. Whitehead Peader N. Kirke James L. Mills George Hooper Roger E. Stevenson Isabel Cordeiro Patricia Correia Temis Felix Rani Gereige Michael L. Cunningham Sonia Canún Stylianos E. Antonarakis Tom Strachan Lap-Chee Tsui Stephen W. Scherer M. Muenke 《Human genetics》1998,102(4):387-392
2.
Barbara Burwinkel Lluis Amat R. George F. Gray Nobutake Matsuo Koji Muroya Kuniaki Narisawa Ronald J. Sokol M. A. Vilaseca M. W. Kilimann 《Human genetics》1998,102(4):423-429
X-linked liver glycogenosis (XLG) resulting from phosphorylase kinase (Phk) deficiency is one of the most common forms of
glycogen storage disease. It is caused by mutations in the gene encoding the liver isoform of the Phk α subunit (PHKA2). In the present study, we address the issue of phenotypic and allelic heterogeneity in XLG. We have identified mutations
in seven male patients. One of these patients represents the variant biochemical phenotype, XLG subtype 2 (XLG2), where Phk
activity is low in liver but normal or even elevated in erythrocytes. He carries a K189E missense mutation, which adds to
the emerging evidence that XLG2 is associated with missense mutations clustering at a few sites. Two patients display clinical
phenotypes unusual for liver Phk deficiency, with dysfunction of the kidneys (proximal renal tubular acidosis) or of the nervous
system (seizures, delayed cognitive and speech abilities, peripheral sensory neuropathy), respectively, in addition to liver
glycogenosis. In the patient with kidney involvement, we have identified a missense mutation (P399S) and a trinucleotide deletion
(2858del3) leading to the replacement of two amino acids by one new residue (N953/L954I), and a missense mutation has also
been found in the patient with neurological symptoms (G1207W). These two cases demonstrate that PHKA2 mutations can also be associated with uncommon clinical phenotypes. Finally, in four typical XLG cases, we have identified
three truncating mutations (70insT, R352X, 567del22) and an in-frame deletion of eight well-conserved amino acids (2452del24).
Together, this study adds eight new mutations to the previously known complement of sixteen PHKA2 mutations. All known PHKA2 mutations but one are distinct, indicating pronounced allelic heterogeneity of X-linked liver glycogenosis with mutations
in the PHKA2 gene.
Received: 17 October 1997 / Accepted: 23 December 1997 相似文献
3.
Tumorigenesis in colorectal tumors from patients with hereditary non-polyposis colorectal cancer 总被引:10,自引:0,他引:10
Tumorigenesis of colorectal cancer in patients with hereditary non-polyposis colorectal cancer (HNPCC) has been postulated
to follow a different pathway from that of sporadic colorectal tumors. A characteristic of HNPCC-associated tumors is the
replication error phenotype. We studied tumorigenesis in 8 fresh-frozen and 67 paraffin-embedded colorectal tumors derived
from 29 families with HNPCC or a familial aggregation of colorectal cancer. By using intragenic markers, inactivation of the
wild-type allele of hMLH1 was shown to occur through loss of heterozygosity and not through a somatic point mutation. Microsatellite instability is
very common and occurs early in almost all colorectal tumors from HNPCC patients. Transforming growth factor β type II receptor
(TβRII) mutations occur in these tumors at a high frequency. Of colorectal cancers from families with HNPCC, 63% have frameshift
mutations in TβRII, compared with 10% of sporadic colorectal cancers. APC and K-RAS mutations appear to be as frequent in the HNPCC tumors as in the sporadic counterpart.
Received: 3 March 1997 / Accepted: 23 June 1997 相似文献
4.
F. Roch F. Serras F. J. Cifuentes M. Corominas B. Alsina M. Amorós A. López-Varea R. Hernández D. Guerra S. Cavicchi J. Bagu?á A. García-Bellido 《Molecular & general genetics : MGG》1998,257(2):103-112
We have carried out screens for lethal mutations on the second chromosome of Drosophila melanogaster that are associated with abnormal imaginal disc morphologies, particularly in the wing disc. From a collection of 164 P element-induced
mutations with a late larva/pupa lethal phase we have identified 56 new loci whose gene products are required for normal wing
disc development and for normal morphology of other larval organs. Genetic mosaics of these 56 mutant lines show clonal mutant
phenotypes for 23 cell-viable mutations. These phenotypes result from altered cell parameters. Causal relationships between
disc and clonal phenotypes are discussed.
Received: 19 June 1997 / Accepted: 4 August 1997 相似文献
5.
A. Tchirkov Jacques-Olivier Bay David Pernin Yves-Jean Bignon Pascale Rio Maria Grancho Fabrice Kwiatkowski Michel Giollant Paul Malet Pierre Verrelle 《Human genetics》1997,101(3):312-316
In ataxia-telangiectasia (A-T) patients, mutations in a single gene, ATM, result in an autosomal recessive syndrome that embraces a variety of clinical features and manifests extreme radiosensitivity
and a strong predisposition to malignancy. Heterozygotes for the ATM gene have no clinical expression of A-T but may be cancer prone with a moderate increase in in vitro radiosensitivity. We
performed a blind chromosomal analysis on G2-phase lymphocytes from 7 unrelated A-T patients, 13 obligate A-T heterozygotes (parents of the patients), and 14 normal controls
following X-irradiation with 1 Gy in order to evaluate this cytogenetic method as a tool for detection of ATM carriers. Both A-T homozygotes and heterozygotes showed significantly increased levels of radiation-induced chromatid damage
relative to that of normal controls. These results show that the G2-phase chromosomal radiosensitivity assay can be used for the detection of A-T heterozygotes. In combination with molecular
genetic analyses, this test may be of value in studies of familial and sporadic cancers aimed at determination of the potential
involvement of ATM mutations in tumor risk or development.
Received: 5 May 1997 / Accepted: 26 August 1997 相似文献
6.
C. A. Satler Mark R. Vesely Priya Duggal G. S. Ginsburg A. H. Beggs 《Human genetics》1998,102(3):265-272
Long QT syndrome (LQTS), is an inherited cardiac disorder in which ventricular tachyarrhythmias predispose affected individuals
to syncope, seizures, and sudden death. Characteristic electrocardiographic findings include a prolonged QT interval, T wave
alternans, and notched T waves. We have screened LQTS patients from 89 families for mutations in the pore region of HERG , the K+ channel gene previously associated with chromosome 7-linked LQT2. In six unrelated LQTS kindreds, single-strand conformation
polymorphism analyses identified aberrant conformers in all affected family members. These conformers were not seen in over
100 unaffected, unrelated control individuals, suggesting that they represent pathogenic LQTS mutations. DNA sequence analyses
of the aberrant conformers demonstrated that they reflect five different missense mutations: V612L, A614V, N629D, N629S, and
N633S. The missense mutation A614V was found in two unrelated families. Further functional studies will be required to determine
what effect each of these changes may have on HERG channel function.
Received: 15 July 1997 / Accepted: 10 November 1997 相似文献
7.
We have found that mutations that lead to loss of rolled/MAP kinase function result in a reduced mitotic index in the larval central nervous system, consistent with an interphase block to cell
cycle progression, associated with a low frequency of cells showing chromosome over-condensation in mitosis and abnormal anaphase
figures. In contrast to wild-type tissue, such rolled mutants do not show a significant increase in accumulation of mitotic cells when treated with colchicine. We have studied
double mutant combinations between mutations affecting the activity of rolled/MAP kinase and several genes that are essential to the establishment of a bipolar spindle during progression through mitosis, and find
no interactions with mutations in polo, mgr,or aurora. However, partial loss-of-function mutations in rolled enhance the abnormal spindle (asp) phenotype, whereas gain-of function mutations in rolled or in the gene encoding its activating kinase Dsor1, act as suppressors. We discuss these findings in relation to the proposed role of MAP kinase in mediating the spindle integrity
checkpoint.
Received: 27 October 1997 / Accepted: 18 December 1997 相似文献
8.
Regina Hühn Heike Stoermer Beate Klingele Elke Bausch Alberto Fois Mariangela Farnetani Maja Di Rocco Joelle Boué Jean M. Kirk Rosalind Coleman G. Scherer 《Human genetics》1998,102(3):305-313
Tyrosinemia typeII (Richner-Hanhart syndrome, RHS) is a disorder of autosomal recessive inheritance characterized by keratitis,
palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in
hepatic tyrosine aminotransferase (TAT). We have previously described one deletion and six different point mutations in four
RHS patients. We have now analyzed the TAT genes in a further seven unrelated RHS families from Italy, France, the United Kingdom, and the United States. We have established
PCR conditions for the amplification of all twelve TAT exons and have screened the products for mutations by direct sequence analysis or by first performing single-strand conformation
polymorphism analysis. We have thus identified the presumably pathological mutations in eight RHS alleles, including two nonsense
mutations (R57X, E411X) and four amino acid substitutions (R119W, L201R, R433Q, R433W). Only the R57X mutation, which was
found in one Scottish and two Italian families, has been previously reported in another Italian family. Haplotype analysis
indicates that this mutation, which involves a CpG dinucleotide hot spot, has a common origin in the three Italian families
but arose independently in the Scottish family. Two polymorphisms have also been detected, viz., a protein polymorphism, P15S,
and a silent substitution S103S (TCG→TCA). Expression of R433Q and R433W demonstrate reduced activity of the mutant proteins.
In all, twelve different TAT gene mutations have now been identified in tyrosinemia typeII.
Received: 8 October 1997 / Accepted: 29 October 1997 相似文献
9.
E. van de Vosse Brunella Franco P. van der Bent Eugenio Montini Ulrike Orth Andre Hanauer N. Tijmes G.-J. B. van Ommen Andrea Ballabio J. T. den Dunnen Arthur A. B. Bergen 《Human genetics》1997,101(2):235-237
X-linked juvenile retinoschisis (RS) is a progressive vitreoretinal degeneration localised in Xp22.1-p22.2. A human homologue
of the retinal degeneration gene C (rdgC), a gene that in Drosophila melanogaster prevents light-induced retinal degeneration, was localised in the RS obligate gene region. We have tested the gene, designated
PPEF in humans, as a candidate gene in RS patients using RT-PCR and the protein truncation test on RNA and SSCP on DNA. No mutations
were identified, making it highly unlikely that PPEF is the gene implicated in RS. The data presented facilitate mutation analysis of the PPEF gene in other diseases which have been or will be localised to this region.
Received: 20 May 1997 / Accepted: 30 July 1997 相似文献
10.
Maria Luisa Ordoñez-Sánchez Salvador Ramírez-Jiménez Antonio Ulises López-Gutierrez Laura Riba Salvador Gamboa-Cardiel Mabel Cerrillo-Hinojosa Nelly Altamirano-Bustamante Raúl Calzada-León Carlos Robles-Valdés Fernando Mendoza-Morfin M. T. Tusié-Luna 《Human genetics》1998,102(2):170-177
Steroid 21-hydroxylase deficiency is the underlying cause in over 90% of patients with congenital adrenal hyperplasia, an
inherited metabolic disorder of adrenal steroidogenesis. We have characterized 94 mutant alleles from 47 unrelated Mexican
patients and the corresponding mutant alleles in their parents by amplification of the functional CYP21 gene by PCR, followed
by direct sequence analysis. The study included patients diagnosed with the three clinical forms of the disease. Our results
revealed: (1) the presence of relatively few mutations or combinations of mutations associated with particular phenotypes;
(2) the presence of putative new mutations; (3) the finding of identical genotypes in patients displaying discordant phenotypes;
(4) the identification of patients lacking all previous reported mutations; and (5) an apparent high frequency of germ-line
mutations. The absence of previously reported mutations in about 22% of the disease alleles, the finding of putative new mutations
in some of the patients lacking previously known mutations, and the apparent high prevalence of germ-line mutations make evident
the differences in the genetic background leading to this disorder between the Caucasian and the Mexican populations.
Received: 11 August 1997 / Accepted: 6 November 1997 相似文献
11.
Kai-Ling Fu Peter C. Thuß Tadahiro Fujino Martin Digweed Johnson M. Liu Christopher E. Walsh 《Human genetics》1998,102(2):166-169
Fanconi anemia (FA) is an autosomal recessive disorder characterized by bone marrow failure, cancer susceptibility, and a
variety of developmental defects. The disease is clinically heterogeneous; eight different complementation groups (FA A–H)
and, thus, genetic loci have been discovered. Two genes, FAA and FAC, have been cloned. Disease-associated mutations have been detected and rapid mutation screening makes possible the assignment
of patients without resorting to time-consuming cell fusion and complementation analysis. Amplification of specific cDNAs
from RNA followed by direct or indirect sequence analysis is a standard method for mutation detection. During the course of
such examinations of the FAC gene, we have noted that frequently only one of the expressed alleles is successfully amplified. This can lead to false assignment
of patients to a complementation group. As we report here, such cases can be rapidly clarified by retroviral gene transfer
and complementation analysis.
Received: 30 July 1997 / Accepted: 13 October 1997 相似文献
12.
We have identified and characterized three embryonic lethal mutations that alter or abolish expression of Drosophila Neuroglian and have used these mutations to analyze Neuroglian function during development. Neuroglian is a member of the immunoglobulin superfamily. It is expressed by a variety of cell types during embryonic development, including expression on motoneurons and the muscle cells that they innervate. Examination of the nervous systems of neuroglian mutant embryos reveals that motoneurons have altered pathfinding trajectories. Additionally, the sensory cell bodies of the peripheral nervous system display altered morphology and patterning. Using a temperature-sensitive mutation, the phenocritical period for Neuroglian function was determined to occur during late embryogenesis, an interval which coincides with the period during which neuromuscular connections and the peripheral nervous system pattern are established. © 1997 John Wiley & Sons, Inc. J Neurobiol 32: 325–340, 1997 相似文献
13.
Anja Klose Peter Nicholas Robinson Andreas Gewies Lan Kluwe Dieter Kaufmann Annegret Buske Sigrid Tinschert H. Peters 《Human genetics》1998,102(3):367-371
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder. It is caused by mutations in the NF1 gene, which comprises
60 exons and is located on chromosome 17q11.2. A total of 170 unrelated NF1 patients were screened for mutations in four exons
by temperature-gradient gel electrophoresis. Preparatory work revealed the presence of a previously uncharacterized intron
(19a) in what was previously designated exon 19; this allowed us to develop assays for genomic mutation screening in the newly
defined exons 19a and 19b. Two novel NF1 mutations were detected: a single-base insertion in exon 19a creating a frameshift,
and a second mutation affecting the splice donor site of intron 20 and leading to skipping of exon 20. A novel BsaBI polymorphism was identified in intron 19a.
Received: 11 August 1997 / Accepted: 13 November 1997 相似文献
14.
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
15.
S. Puig Anna Ruiz Teresa Castel Victor Volpini Josep Malvehy Francesc Cardellach Michael Lynch Jose M. Mascaro Xavier Estivill 《Human genetics》1997,101(3):359-364
Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma
(CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though
the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer
associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and
nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests
that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer.
Received: 2 June 1997 / Accepted: 11 August 1997 相似文献
16.
The development of external sensory organs on the notum of Drosophila is promoted by the proneural genes achaete and scute. Their activity defines proneural cell clusters in the wing imaginal disc. Ectopic expression, under control of the GAL4 system, of the proneural gene lethal of scute (l'sc) causes the development of ectopic bristles. Persistent ectopic expression of l'sc is not sufficient to impose a neural fate on any given cell. This implies that mutual inhibition, mediated by the Notch signaling pathway, occurs among the cells of the ectopic proneural cluster. Consequently, the dominant, quantifiable phenotype
associated with ectopic expression of l'sc is modified by mutations in genes known to be involved in neurogenesis. This phenotype has been utilized to screen for dominant
enhancers and suppressors that modify the number of ectopic bristles. In this way, about 100 000 progeny of EMS or X-ray-treated
flies have been analyzed to identify autosomal genes involved in regulation of the neural fate. In addition 1200 chromosomes
carrying lethal P-element insertions were screened for modifiers. Besides mutations in genes expected to modify the phenotype,
we have isolated mutations in six genes not known so far to be involved in neurogenesis.
Received: 20 September 1997 / Accepted: 8 October 1997 相似文献
17.
To identify proteins that interact directly or indirectly with the NUDF protein, which is required for nuclear migration
in Aspergillus nidulans, we initiated a screen for extragenic suppressors of the heat-sensitive nudF6 mutation. Suppressor mutations in at least five genes, designated snfA–snfE, caused improved growth and nuclear migration at high temperatures compared to the nudF6 parent. Two snfC mutations mapped near the nudA gene, which encodes the cytoplasmic dynein heavy chain, and could be repaired by transformation with wild-type nudA DNA, demonstrating that they are mutations in nudA. The snfC mutations are bypass suppressors of nudF and genetic evidence indicated that NUDA and NUDF act in the same nuclear migration pathway. Taken together, our data suggests
that NUDF affects nuclear migration by acting on the dynein motor system.
Received: 4 January 1997 / Accepted: 26 February 1997 相似文献
18.
M. Ludwig Ursula Bolkenius Lucia Wickert Peter Marynen Frank Bidlingmaier 《Human genetics》1998,102(5):576-581
The human amiloride-sensitive epithelial sodium channel (ENaC) is a member of the degenerin/ENaC family of ion channels and
regulates fluid and electrolyte absorption across a number of epithelia, including kidney, colon and lung. Native ENaC has
been shown to be a multimer made up of at least three homologous subunits (α, β, γ) and mutations affecting the channel complex
have been identified in various human diseases. “Gain of function” mutations in one of the three ENaC subunits have been found
to cause pseudoaldosteronism (Liddle’s syndrome) and ENaC “reduction of function” mutations are found in patients affected
with the recessive form of pseudohypoaldosteronism (PHA) type 1. In this report, we describe the genomic organisation of the
humanαENaC gene. Human αENaC consists of 13 exons spanning 17 kb on chromosome 12p13 and contains at least eight Alu sequences. In addition to the intron/exon
boundaries, we have deciphered almost all the intron sequences and 475 bp of the CCAAT-less and TATA-less 5′ flanking region.
Received: 23 December 1997 / Accepted: 5 March 1998 相似文献
19.
D. Sheluho M. J. Yebra S. S. Khariwala A. S. Bhagwat 《Molecular & general genetics : MGG》1997,255(1):54-59
The cytosine methyltransferases (MTases) M. HhaIand M. HpaII bind substrates in which the target cytosine is replaced by uracil or thymine, i.e. DNA containing a U:G or a T:G mismatch.
We have extended this observation to the EcoRII MTase (M. EcoRII) and determined the apparent Kd for binding. Using a genetic assay we have also tested the possibility that MTase binding to U:G mismatches may interfere
with repair of the mismatches and promote C:G to T:A mutations. We have compared two mutants of M. EcoRII that are defective for catalysis by the wild-type enzyme for their ability to bind DNA containing U:G or T:G mismatches
and for their ability to promote C to T mutations. We find that although all three proteins are able to bind DNAs with mismatches,
only the wild-type enzyme promotes C:G to T:A mutations in vivo. Therefore, the ability of M. EcoRII to bind U:G mismatched duplexes is not sufficient for their mutagenic action in cells.
Received: 14 November 1996 / Accepted: 17 February 1997 相似文献
20.
Graça Porto Helena Alves Pedro Rodrigues José M Cabeda Cristina Portal Anunciação Ruivo Benvindo Justiça Roger Wolff Maria De Sousa 《Immunogenetics》1998,47(5):404-410
The present study is an analysis of the frequencies of HFE mutations in patients with different forms of iron overload compared with the frequencies found in healthy subjects from
the same region. The frequencies of HLA-A and -B antigens and HLA haplotypes were also analyzed in the same subjects. The study population included: 71 healthy individuals; 39 genetically
and clinically well-characterized patients with genetic hemochromatosis (HH); and 25 patients with non-classical forms of
iron overload (NCH), excluding secondary hemochromatosis. All subjects were HLA-typed and HFE-genotyped by the oligonucleotide ligation assay (OLA). The gene frequencies found for the C282Y and H63D mutations of HFE were respectively: 0.03 and 0.23 in healthy individuals, 0.86 and 0.04 in HH patients, and 0.08 and 0.48 in NCH patients.
An expected significant association between HH and HLA-A3 was observed, which was found to be in linkage disequilibrium with
the C282Y mutation. A new association was seen, however, between HLA-A29 and NCH, in linkage disequilibrium with the H63D
mutation. Again as expected, the HLA-B antigen B7 was associated with HH in linkage disequilibrium with HLA-A3. In addition,
the HLA-B antigen B44 was found to be associated with NCH but not in linkage disequilibrium with either A29 or the H63D mutation.
In conclusion, a new association of the HFE H63D mutation with forms of hemochromatosis other than HH and a new association between the HLA phenotype A29 and the HFE H63D mutation were found in the same patients. These findings reinforce evidence for the involvement of the major histocompatibility
class I in iron metabolism, supporting the notion of a physiological role for the immunological system in the regulation of
iron load.
Received: 11 June 1997 / Revised: 29 October 1997 相似文献