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1.
Horinishi A Okubo M Tang NL Hui J To KF Mabuchi T Okada T Mabuchi H Murase T 《Journal of human genetics》2002,47(2):55-59
Glycogen storage disease type III (GSD III) is a rare autosomal recessive inherited disorder caused by a deficiency of the
glycogen-debranching enzyme (AGL). We investigated two GSD III patients and identified four different mutations. Nucleotide
sequence analysis revealed patient 1 of Chinese descent to be a compound heterozygote for a novel nonsense mutation, R34X,
and the splicing mutation (IVS32−12A > G) reported in a Japanese patient. Patient 2 of Japanese origin was found to be compound
heterozygous for a novel nonsense mutation, Y1148X, and the splicing mutation (IVS14+1G > T) that we had described previously.
To determine whether splicing mutations occurred independently, we performed intense AGL haplotype analysis using 21 intragenic
polymorphic markers plus a novel polymorphism IVS32−97 A/G in the vicinity of the IVS32 splicing mutation. Patient 1 of Chinese
origin and the Japanese patient homozygous for the IVS32−12A > G were found to have different haplotypes, indicating the IVS32−12A
> G mutation to be a recurrent mutation. This is the first recurrent mutation established by intense haplotyping in the AGL gene.
Received: October 3, 2001 / Accepted: November 12, 2001 相似文献
2.
Bruton's tyrosine kinase (BTK) is involved in B-cell development. Mutation of BTK results in X-linked agammaglobulinemia (XLA). BTK is expressed in most haemopoietic lineages except mature T cells and plasma cells. We identified six novel and two known mutations of BTK in 11 Chinese XLA patients from 8 families. Family 1 had a novel point mutation at the start codon (135G-->T) in exon 2. Family 2 had known mutation of single A insertion in a stretch of 7 A residues (341-347insA) recognized as mutation hotspot in exon 3. Family 3 had a novel point mutation in exon 11 (1074A-->G) which led to aberrant splicing. Family 4 had known mutation in exon 19 (2053C-->T) in CpG mutation hotspot. The novel mutation of family 5 was an A deleted in a run of three As (1017-1019delA) in exon 10. In family 6, exons 2 and 3 were lost in BTK mRNA, a novel deletion. Family 7 had a novel substitution in exon 2 (227T-->C) which led to change of a conserved leucine to serine. Family 8 had a novel point mutation at beginning of intron 14 (IVS14+ 6 T-->G) resulting in aberrant splicing. Hum Mutat 15:385, 2000. 相似文献
3.
Yue Wang Hirokazu Kanegane Ozden Sanal Fügen Ersoy Ilhan Tezcan Takeshi Futatani Satoshi Tsukada Toshio Miyawaki 《Human mutation》2001,18(4):356-356
X‐linked agammglobulinemia (XLA) is a ptototypical humoral immunodeficiency caused by mutations in the gene coding for Bruton tyrosine kinase (BTK). The genetic defect in XLA impairs early B cell development resulting in marked reduction of mature B cells in the blood. Studies from different countries have demonstrated that approximately 90% of males with presumed XLA bear mutations in BTK. In this study, we report for the first time the occurrence of BTK mutations in Turkey. We performed mutational analysis of the BTK gene in 16 Turkish male patients from 13 separate families with presumed XLA based on abnormally low peripheral blood B‐cell numbers (lt; 1%), hypogammaglobulinemia, and recurrent bacterial infections. We found that in nine of the 13 families (69%) a Btk mutation caused XLA. Two of the mutations were previously described, but seven novel mutations were identified: two missense (Y39C, G584R), one nonsense (Q343X), and 4 deletions (1800‐1821del, 1843‐1847del, 1288‐1292del, 291del) resulting in frameshift and premature stop codon. By contrast, no mutations in the BTK gene were identified in the other 4 families. A consanguinity in three of these families raises the possibility that mutations in other autosomal genes which affect early B cell development may contribute to their phenotype resembling XLA. Hum Mutat 18:356, 2001. © 2001 Wiley‐Liss, Inc. 相似文献
4.
Ramos-Trujillo E González-Acosta H Flores C García-Nieto V Guillén E Gracia S Vicente C Espinosa L Maseda MA Santos F Camacho JA Claverie-Martín F 《Journal of human genetics》2007,52(3):255-261
Mutations in the voltage-gated chloride/proton antiporter ClC-5 gene, CLCN5, are associated with Dent’s disease, an X-linked renal tubulopathy. Our interest is to identify and characterize disease-causing
CLCN5 mutations, especially those that alter the splicing of the pre-mRNA. We analyzed the CLCN5 gene from nine unrelated Spanish Dent’s disease patients and their relatives by DNA sequencing. Pre-mRNA splicing analysis
was performed by RT-PCR. Seven new mutations were identified, consisting of three missense mutations (C219R, F273L, and W547G),
one splice-site mutation (IVS-2A > G), one deletion (976delG), and two non-sense mutations (Y140X and W314X). We found that
missense mutation W547G also led to increased expression of a new alternative isoform lacking exons 10 and 11 that was expressed
in several human tissues. In addition, we describe another novel CLCN5 splicing variant lacking exon 11 alone, which was expressed only in human skeletal muscle. We conclude that missense mutation
W547G can also alter the expression levels of a CLCN5 mRNA splicing variant. This type of mutation has not been previously described in the CLCN5 gene. Our results support the importance of a routine analysis at the pre-mRNA level of mutations that are commonly assumed
to cause single amino acids alterations. 相似文献
5.
Fofanova OV Evgrafov OV Polyakov AV Peterkova VA Dedov II 《Bulletin of experimental biology and medicine》2006,141(3):347-352
Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations
of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone
deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant
negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 −2A>T, IVS3
+2T>C, and IVS3 +1G<A. GH-1 is the main gene of type II isolated growth hormone deficiency in patients living in the Russian Federation. All detected
mutations of GH-1 impair splicing processes, which distinguishes them from mutations in other forms of isolated growth hormone deficiency.
The detected variety of GH-1 splicing mutations attests to allele genetic heterogeneity of this pathology. The “hot spot” of mutations is 5′-donor splicing
site of GH-1 intron 3, while IVS3 +1G>A mutation can be regarded as the most incident in type II isolated growth hormone deficiency in
the Russian population.
__________
Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 3, pp. 324–329, March, 2006 相似文献
6.
7.
Ma Cruz García Rodríguez Eduardo Lpez Granados Antonio Ferreira Cerdn Gumersindo Fontn Casariego 《Human mutation》2001,18(1):84-84
Mutations in Bruton’s tyrosine kinase (BTK) gene result in X linked agammaglobulinemia (XLA). Using Single Strand Conformation Polymorphism (SSCP) followed by direct sequencing 21 mutations were found in 27 patients with an XLA phenotype from 21 unrelated families. We identified 13 novel and 8 known mutations: seven missense (R288W, R544G, P566S, K430E; K374N, L512P, R544S), 5 nonsense (Q196X, Y361X, L249X, Q612X, Q466X), 2 deletions of one nucleotide (A207fsX216, Q612fsX648), 2 deletion‐insertions (V219fsX227, K218fsX228), one insertion of two nucleotides (S572fsX587) and 4 point mutations in donor/acceptor splice sites (g.IVS1+1G>C, g.IVS6+5G>A, g.IVS10+1G>T, g.IVS13‐1GG>CT). Carrier detection was performed in 18 mothers. Only in one case the mutation was found to be de novo. Additionally, BTK mutations were not found in four patients without family history, but with XLA‐compatible phenotype. Hum Mutat 18:84, 2001. © 2001 Wiley‐Liss, Inc. 相似文献
8.
M.D. Bashyam A.K. Chaudhary M. Kiran V. Reddy H.A. Nagarajaram A. Dalal L. Bashyam D. Suri A. Gupta N. Gupta M. Kabra R.D. Puri R. RamaDevi S. Kapoor S. Danda 《Clinical genetics》2014,86(6):530-538
Farber lipogranulomatosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the ASAH1 gene. In the largest ever study, we identified and characterized ASAH1 mutations from 11 independent Farber disease (FD) families. A total of 13 different mutations were identified including 1 splice, 1 polypyrimidine tract (PPT) deletion and 11 missense mutations. Eleven mutations were exclusive to the Indian population. The IVS6+4A>G splice and IVS5‐16delTTTTC PPT deletion mutations resulted in skipping of exon 6 precluding thereby the region responsible for cleavage of enzyme precursor. A missense mutation (p.V198A) resulted in skipping of exon 8 due to inactivation of an exonic splicing enhancer (ESE) element. This is the first report of mutations affecting PPT and ESE in the ASAH1 gene resulting in FD. 相似文献
9.
Two novel mutations of the β-hexosaminidase α subunit gene were identified in Japanese patients with the infantile form of
Tay-Sachs disease. One mutation was a one-base deletion at nt613C, which generated a stop codon at two codons downstream,
in three unrelated patients. The other mutation was a one-base substitution of G-to-A at IVS 5, +1, which caused a splicing
abnormality, in one patient. A missense mutation of R170W, which has already been reported in other ethnic groups, was also
newly identified in one patient. In 1993, the most common mutation (IVS 5, −1G → T) in Japanese patients with Tay-Sachs disease
was reported as the major mutation in Japan accounting for 80% of 56 mutant alleles from 28 unrelated patients. The deletion
of nt613C was the second most common mutation, accounting for 5% of the mutant alleles. The previously reported mutation IVS
5, −1G → T and the nt613C deletion found in this study together accounted for 85% of the mutations causing Tay-Sachs disease
among Japanese. Since these two mutations were located in or close to exon 6 and since they abolish Fok I (IVS 5, −1G → T) and Sfa NI (nt613C deletion) restriction sites, respectively, they were screened rapidly by single polymerase chain reaction followed
by digestion with these enzymes.
Received: November 10, 1998 / Accepted November 14, 1998 相似文献
10.
Pääkkönen K Cambiaghi S Novelli G Ouzts LV Penttinen M Kere J Srivastava AK 《Human mutation》2001,17(4):349
Mutations in ectodysplasin, the protein product of the EDA or ED1 gene, cause X-linked anhidrotic ectodermal dysplasia. From sixteen families we have identified thirteen mutations, of which nine were novel: a deletion of the entire exon 1, altered splicing site in intron 7 (IVS-2A-->G) and in intron 9 (IVS9+8 C-->G), deletion of 8 bp (1967-1974 nt), four missense mutations (G255C, G255D, W274G, C332Y) and nonsense mutation W274X. Previously identified and the novel mutations form four clusters: 1) at the junction of the transmembrane and extracellular domains, 2) at a putative protease recognition site, possibly affecting cleavage of ectodysplasin, 3) at the trimerizing collagen-like domain, and 4) at regions of high homology to tumor necrosis factor domains. Truncating and splice site mutations occur within the proximal two-thirds of the protein. Our data suggest the functional importance of specific ectodysplasin domains. Hum Mutat 17:349, 2001. 相似文献
11.
Adriana De Siervi Manuel Mendez Victoria Estela Parera Laura Varela Alcira M. del C. Batlle Maria Victoria Rossetti 《Human mutation》1999,14(4):355-355
A partial deficiency of Porphobilinogen deaminase (PBG‐D) is responsible for acute intermittent porphyria (AIP). AIP is inherited in an autosomal dominant fashion, and the prevalence in the Argentinean population is about 1:125,000. Here, two new mutations and three previously reported were found in the PBG‐D gene in 12 Argentinean AIP patients corresponding to 5 different families. To screen for AIP mutations in symptomatic patients, genomic DNA isolated was amplified in 2 Multiplex PCR reactions, then all coding exons and flanking intronic regions were sequenced. The new mutations are 453‐455delAGC in exon 9 which results in the loss of an alanine residue at position 152, and one new point mutation in the splicing aceptor site in the last position of intron 8 (IVS8‐1G>T) which leds to a 15 bp deletion because a cryptic site (first AG upstream) is used. Both mutations produce amino acid deletion without frameshift effect. To further characterize the 453‐455delAGC mutation, the pKK‐PBGD construct for the mutant allele was expressed in E. coli, the enzymatic activity of the recombinant protein was 1.3% of the mean level expressed by the normal allele. Finally, three missense mutations, previously reported, were identified in three unrelated families. Hum Mutat 14:355, 1999. © 1999 Wiley‐Liss, Inc. 相似文献
12.
Novel donor splice site mutation of ABCG5 gene in sitosterolemia 总被引:2,自引:0,他引:2
In a patient with sitosterolemia, we found two different mutations of the ATP-binding cassette, subfamily G, member 5 (ABCG5) gene. The first is a missense mutation that changes the amino acid residue at position 419 from arginine to histidine, i.e., R419H. The second is a novel splicing mutation affecting the invariant guanine at the first base of the donor splice site of intron 12, i.e., IVS12 + 1G --> A. The father of the patient is heterozygous for the missense mutation, and the mother is heterozygous for the splicing mutation. No mutations were found in the sister of the patient. Up until now, the missense mutation has only been found in Japanese patients with sitosterolemia. We believe that R419H in our Chinese patient may have the same origin as the mutation in the Japanese patients with sitosterolemia. 相似文献
13.
Mutations in the gene encoding fibrillin-1 (FBN1) cause Marfan syndrome (MFS) and other related connective tissue disorders. In this study we performed SSCP to analyze all 65 exons of the FBN1 gene in 76 patients presenting with classical MFS or related phenotypes. We report 7 missense mutations, 3 splice site alterations, one indel mutation, one nonsense mutation and two mutations causing frameshifts: a 16bp deletion and a single nucleotide insertion. 5 of the missense mutations (Y1101C, C1806Y, T1908I, G1919D, C2251R) occur in calcium-binding Epidermal Growth Factor-like (EGFcb) domains of exons 26, 43, 46 and 55, respectively. One missense mutation (V449I) substitutes a valine residue in the non-calcium-binding epidermal growth factor like domain (EGFncb) of exon 11. One missense mutation (G880S) affects the "hybrid" motif in exon 21 by replacing glycine to serine. The 3 splice site mutations detected are: IVS1-1G>A in intron 1, IVS38-1G>A in intron 38 and IVS46+5G>A in intron 46. C628delinsK was identified in exon 15 leading to the substitution of a conserved cysteine residue. Furthermore two frameshift mutations were found in exon 15 (1904-1919del ) and exon 63 (8025insC) leading to premature termination codons (PTCs) in exon 17 and 64 respectively. Finally we identified a nonsense mutation (R429X) located in the proline rich domain in exon 10 of the FBN1 gene. Y1101C, IVS46+5G>A and R429X have been reported before. 相似文献
14.
Chikumi H Yamamoto T Ohta Y Nanba E Nagata K Ninomiya H Narasaki K Katoh T Hisatome I Ono K Tanaka Y Kuroda H Ohgi S 《Journal of human genetics》2000,45(2):115-118
Marfan syndrome (MFS; MIM #154700) is a connective tissue disorder characterized by cardiovascular, skeletal, and ocular
abnormalities. The fibrillin-1 gene (FBN1; MIM no. 134797) on chromosome 15 was revealed to be the cause of Marfan syndrome. To date over 137 types of FBN1 mutations have been reported. In this study, two novel mutations and a recurrent de-novo mutation were identified in patients
with MFS by means of single-strand conformational polymorphism (SSCP) analysis. The two novel mutations are a 4-bp deletion
at nucleotide 2820-2823 and a G-to-T transversion at nucleotide 1421 (C474F), located on exon 23 and exon 11, respectively.
A previously reported mutation at the splicing donor site of intron 2 (IVS2 G + 1A), which is predicted to cause exon skipping,
was identified in a sporadic patient with classical MFS.
Received: November 1, 1999 / Accepted: November 9, 1999 相似文献
15.
Zoran Gatalica MD DSc Stan L. Lilleberg PhD Semir Vranic MD Eduardo Eyzaguirre MD Eduardo Orihuela MD Gopalrao Velagaleti PhD 《Human pathology》2009,40(12):1813-1819
Multiple renal tumors of diverse morphology are rare and typically seen in Birt-Hogg-Dubé syndrome. Birt-Hogg-Dubé syndrome is a rare inherited cancer syndrome caused by a germline mutation in the folliculin (FLCN) gene, but the genetic causes for histologic diversity of renal tumors in Birt-Hogg-Dubé syndrome have not been elucidated. We describe here a 64-year-old man with a novel germline mutation in the FLCN gene who presented with 3 phenotypically distinct renal tumors in the same kidney, which were histologically classified as oncocytoma (1.4 cm), oncocytic papillary carcinoma (0.5 cm), and clear cell renal carcinoma (0.8 cm). Genetic analysis of normal kidney tissue revealed a heterozygous germline FLCN mutation (intron 9, IVS9+6 C>T). Additional molecular genetic testing revealed somatic mutations and epigenetic events in genes typically associated with these specific histologic tumor types: oncocytoma harbored a second FLCN mutation (intron 12, IVS12+4 C>T), oncocytic papillary carcinoma harbored promoter methylation of FLCN, and a missense mutation in the MET gene (P246L), whereas clear cell carcinoma harbored inactivating VHL mutation (5–base pair deletion in exon 2) and VHL gene promoter methylation. In addition, chromosomal analysis of peripheral blood lymphocytes showed low level chromosome instability, not previously associated with germline mutations in the FLCN gene. 相似文献
16.
A novel mechanism of aberrant pre-mRNA splicing in humans 总被引:4,自引:2,他引:4
Cogan JD; Prince MA; Lekhakula S; Bundey S; Futrakul A; McCarthy EM; Phillips JA rd 《Human molecular genetics》1997,6(6):909-912
17.
Sedivá A Smith CI Asplund AC Hadac J Janda A Zeman J Hansíková H Dvoráková L Mrázová L Velbri S Koehler C Roesch K Sullivan KE Futatani T Ochs HD 《Journal of clinical immunology》2007,27(6):640-646
X-linked agammaglobulinemia (XLA) is characterized by low levels of B-lymphocytes with early-onset, recurrent, microbial infections
occasionally causing neurological symptoms. We observed an atypical clinical course of XLA, complicated since early childhood
with neurological impairment, progressive sensorineural deafness, and dystonia in six boys of four unrelated families. The
neurologic symptoms suggested the diagnosis of Mohr–Tranebjaerg syndrome, caused by mutations in the TIMM8A gene, previously known as DDP1, and located centromerically of BTK. Deafness dystonia peptide (DDP1) participates in neurological development and is a part of the mitochondrial protein import
pathway. Mutation analysis of the BTK gene revealed gross deletions of different lengths in all patients, in one case extending approximately 196 kb, including
the genes TIMM8A, TAF7L, and DRP2. The most prominent clinical findings of this contiguous deletion syndrome are the combination of immunodeficiency and sensorineural
deafness, which were present in all affected boys. The severity of symptoms, however, did not correlate with the extent of
the deletion. 相似文献
18.
19.
Asako Horinishi Yoichi Suzuki Toshio Murase Kiyoshi Hayasaka 《American journal of medical genetics. Part A》2000,93(3):211-214
Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency of glycogen‐debranching enzyme (AGL). We studied a 2‐year‐old GSD III patient whose parents were from different ethnic groups. Nucleotide sequence analysis of the patient showed two novel mutations: a single cytosine deletion at nucleotide 2399 (2399delC) in exon 16, and a G‐to‐A transition at the +5 position at the donor splice site of intron 33 (IVS33+5G>A). Analysis of the mRNA produced by IVS33+5G>A showed aberrant splicing: skipping of exon 33 and activation of a cryptic splice site in exon 34. Mutational analysis of the family revealed that the 2399delC was inherited from her father, who is of Japanese origin, and the IVS33+5G>A from her mother, who is of Chinese descent, establishing that the patient was a compound heterozygote. To our knowledge, this is the first report of a mutation identified in a GSD III patient from the Chinese population. Am. J. Med. Genet. 93:211–214, 2000. © 2000 Wiley‐Liss, Inc. 相似文献
20.