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1.
Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene 总被引:1,自引:0,他引:1
Katie L. Swango Mübeccel Demirkol Gülden Hüner E. Pronicka Jolanta Sykut-Cegielska Andreas Schulze B. Wolf 《Human genetics》1998,102(5):571-575
Newborn screening for biotinidase deficiency has identified children with profound biotinidase deficiency (<10% of mean normal
serum activity) and those with partial biotinidase deficiency (10%–30% of mean normal serum activity). Children with partial
biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e.,
prolonged infection). We found that 18 of 19 randomly selected individuals with partial deficiency have the transversion missense
mutation G1330>C, which substitutes a histidine for aspartic acid444 (D444H) in one allele of the biotinidase gene. We have
previously estimated that the D444H mutation results in 48% of normal enzyme activity for that allele and occurs with an estimated
frequency of 0.039 in the general population. The D444H mutation in biotinidase deficiency is similar to the Duarte variant
in galactosemia. The D444H mutation in one allele in combination with a mutation for profound deficiency in the other allele
is the common cause of partial biotinidase deficiency.
Received: 8 December 1997 / Accepted: 22 January 1998 相似文献
2.
Biochemical and immunological characterization of serum biotinidase in profound biotinidase deficiency. 下载免费PDF全文
The biochemical and immunological characterization of biotinidase was performed in sera from 100 normal individuals, 68 children with profound biotinidase deficiency (less than 10% of mean normal activity) who were identified symptomatically and by newborn screening, and 63 of their parents. On isoelectric focusing, serum enzyme from normal individuals exhibits extensive microheterogeneity, consisting of at least four major and five minor isoforms at pH 4.15-4.35. Patients with profound biotinidase deficiency can be classified into at least nine distinct biochemical phenotypes, on the basis of (a) the presence or absence of cross-reacting material (CRM) to biotinidase, (b) the number of isoforms, and (c) the distribution frequency of the isoforms. None of the patients with CRM had an abnormal Km of the substrate for the enzyme. All of the parents had normal isoform patterns. The mean activities, CRM concentrations, and specific activities were not significantly different between parents of CRM-positive children and parents of CRM-negative children. There is no relationship between either the age at onset or the severity of symptoms and the isoform patterns or CRM status of the symptomatic children. The isoform patterns of children identified by newborn screening are not different from those of symptomatic children. 相似文献
3.
P S Hart B O Barnstein J R Secor McVoy R Matalon B Wolf 《Biochemical medicine and metabolic biology》1992,48(1):41-45
We describe a method for more accurately determining residual biotinidase activity in sera of individuals with profound biotinidase deficiency. Using this method we found that there is a statistically significant difference in the means of residual serum enzyme activities of symptomatic children and those identified by newborn screening. A subgroup of children identified by screening have activities higher than any of the symptomatic population. These children may develop mild symptoms, may develop symptoms later in life, or may not develop symptoms at all. 相似文献
4.
Heath Cole Knight Thomas R. Reynolds Gregory A. Meyers Robert J. Pomponio Gregory A. Buck Barry Wolf 《Mammalian genome》1998,9(4):327-330
Biotinidase cleaves biotin from biocytin, thereby recycling the vitamin. We have determined the structure of the human biotinidase
gene. A genomic clone, containing three exons that code for the mature enzyme, was obtained by screening a human genomic bacteriophage
library with the biotinidase cDNA by plaque hybridization. To obtain a clone containing the most 5′ exon of the biotinidase
cDNA, a human PAC library by PCR was screened. The human biotinidase gene is organized into four exons and spans at least
23 kb. The 5′-flanking region of exon 1 contains a CCAAT element, three initiator sequences, an octamer sequence, three methylation
consensus sites, two GC boxes, and one HNF-5 site, but has no TATA element. The region from nt −600 to +400 has features of
a CpG island and resembles a housekeeping gene promoter. The structure and sequence of this gene are useful for identifying
and characterizing mutations that cause biotinidase deficiency.
Received: 30 September 1997 / Accepted: 5 December 1997 相似文献
5.
A. Tiar A. Mekki M. Nagara F. Ben Rhouma O. Messaoud N. Ben Halim R. Kefi M.T. Hamlaoui A. Lebied S. Abdelhak 《Gene》2014
Biotinidase deficiency is an autosomal recessive disorder of biotin metabolism leading to varying degrees of neurologic and cutaneous symptoms when untreated. In the present study, we report the clinical features and the molecular investigation of biotinidase deficiency in four unrelated consanguineous Algerian families including five patients with profound biotinidase deficiency and one child characterized as partial biotinidase deficiency. Mutation analysis revealed three novel mutations, c.del631C and c.1557T>G within exon 4 and c.324-325insTA in exon 3. Since newborn screening is not available in Algeria, cascade screening in affected families would be very helpful to identify at risk individuals. 相似文献
6.
M. Y. Tsai M. Bignell K. Schwichtenberg N. Q. Hanson 《American journal of human genetics》1996,59(6):1262-1267
We found that a mutation previously described by Sebastio et al., involving a 68-bp insertion in the coding region of exon 8 of the cystathionine-beta-synthase (CBS) gene in a single patient with homocystinuria, is highly prevalent. In our control population, 11.7% (9/77) of the individuals were heterozygous carriers of this mutation. In contrast to the previous report, which assumed that the 68-bp insertion introduced a premature-termination codon and resulted in a nonfunctional CBS enzyme, we found that the presence of this mutation is not associated with hyperhomocysteinemia. Assay of CBS activity in transformed lymphocytes from individuals who were heterozygous or homozygous for this mutation showed normal activity. Furthermore, reverse-transcripion-PCR showed that individuals carrying this mutation have normal size mRNA. Our results suggest that the insertion creates an alternate splicing site, which eliminates not only the inserted intronic sequences but also the T833C mutation associated with this insertion. The net result is the generation of both quantitatively and qualitatively normal mRNA and CBS enzyme. Although the mutation does not seem to affect the activity of the CBS enzyme, the prevalence is somewhat increased in patients with premature coronary-artery disease, although the difference is not statistically significant. 相似文献
7.
Reinhard Schneppenheim Kathy B. Thomas Sonja Krey Ulrich Budde Ursula Jessat Anton H. Sutor Barbara Zieger 《Human genetics》1995,95(6):681-686
A screening project to identify candidate molecular defects causing von Willebrand disease type IIC (VWD IIC) in a German family was carried out using polymerase chain reaction (PCR) amplification of all 52 exons of the von Willebrand factor (VWF) gene, subsequent electrophoresis of single and double stranded DNA and direct sequencing of PCR products with aberrant electrophoretic patterns. Only one candidate mutation, G550R, caused by a GA transition, was detected in exon 14 of the pro-VWF gene sequence. This mutation was not found on 200 chromosomes of normal individuals. The propositus was homozygous for the mutation and for an extended intragenic haplotype, composed of eight polymorphic markers. Further family members were heterozygous for the mutation and were phenotypically normal or only mildly affected, in accordance with the recessive pattern of inheritance for VWD type IIC. The mutation could influence one of the presumed active centers for the suspected multimerizing enzymatic activity of pro-VWF localized in the D1 and D2 domain, which corresponds to exon 5 and exon 14 of the VWF gene. 相似文献
8.
Clara?D. van?Karnebeek William?S. Sly Colin?J. Ross Ramona Salvarinova Joy Yaplito-Lee Saikat Santra Casper Shyr Gabriella?A. Horvath Patrice Eydoux Anna?M. Lehman Virginie Bernard Theresa Newlove Henry Ukpeh Anupam Chakrapani Mary?Anne Preece Sarah Ball James Pitt Hilary?D. Vallance Marion Coulter-Mackie Hien Nguyen Lin-Hua Zhang Amit?P. Bhavsar Graham Sinclair Abdul Waheed Wyeth?W. Wasserman Sylvia Stockler-Ipsiroglu 《American journal of human genetics》2014,94(3):453-461
Four children in three unrelated families (one consanguineous) presented with lethargy, hyperlactatemia, and hyperammonemia of unexplained origin during the neonatal period and early childhood. We identified and validated three different CA5A alterations, including a homozygous missense mutation (c.697T>C) in two siblings, a homozygous splice site mutation (c.555G>A) leading to skipping of exon 4, and a homozygous 4 kb deletion of exon 6. The deleterious nature of the homozygous mutation c.697T>C (p.Ser233Pro) was demonstrated by reduced enzymatic activity and increased temperature sensitivity. Carbonic anhydrase VA (CA-VA) was absent in liver in the child with the homozygous exon 6 deletion. The metabolite profiles in the affected individuals fit CA-VA deficiency, showing evidence of impaired provision of bicarbonate to the four enzymes that participate in key pathways in intermediary metabolism: carbamoylphosphate synthetase 1 (urea cycle), pyruvate carboxylase (anaplerosis, gluconeogenesis), propionyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase (branched chain amino acids catabolism). In the three children who were administered carglumic acid, hyperammonemia resolved. CA-VA deficiency should therefore be added to urea cycle defects, organic acidurias, and pyruvate carboxylase deficiency as a treatable condition in the differential diagnosis of hyperammonemia in the neonate and young child. 相似文献
9.
Mutations in argininosuccinate synthetase mRNA of Japanese patients,causing classical citrullinemia.
K. Kobayashi N. Shaheen H. Terazono T. Saheki 《American journal of human genetics》1994,55(6):1103-1112
Citrullinemia is an autosomal recessive disease caused by a genetic deficiency of argininosuccinate synthetase. In order to characterize mutations in Japanese patients with classical citrullinemia, RNA isolated from 10 unrelated patients was reverse-transcribed, and cDNA amplified by PCR was cloned and sequenced. The 10 mutations identified included 6 missense mutations (A118T, A192V, R272C, G280R, R304W, and R363L), 2 mutations associated with an absence of an exon 7 or exon 13, 1 mutation with a deletion of the first 7 bp in exon 16 (which might be caused by abnormal splicing), and 1 mutation with an insertion of 37 bp within exons 15 and 16 in cDNA. The insertion mutation and the five missense mutations (R304W being excluded) are new mutations described in the present paper. These are in addition to 14 mutations (9 missense mutations, 4 mutations associated with an absence of an exon in mRNA, and 1 splicing mutation) that we identified previously in mainly American patients with neonatal citrullinemia. Two of these 20 mutations, a deletion of exon 13 sequence and a 7-bp deletion in exon 16, were common to Japanese and American populations from different ethnic backgrounds; however, other mutations were unique to each population. Furthermore, the presence of a frequent mutation--the exon 7 deletion mutation in mRNA, which accounts for 10 of 23 affected alleles--was demonstrated in Japanese citrullinemia. This differs from the situation in the United States, where there was far greater heterogeneity of mutations. 相似文献
10.
Tsukamoto H Horiuchi T Kokuba H Nagae S Nishizaka H Sawabe T Harashima S Himeji D Koyama T Otsuka J Mitoma H Kimoto Y Hashimura C Kitano E Kitamura H Furue M Harada M 《Biochemical and biophysical research communications》2005,330(1):298-304
A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84bp). A single base substitution (AG to GG) in the 3'-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Delta(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Delta(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3. 相似文献
11.
Deficiency of the ninth component of human complement (C9) is the most common complement deficiency in Japan but is rare
in other countries. We studied the molecular basis of C9 deficiency in four Japanese C9-deficient patients who had suffered
from meningococcal meningitis. Direct sequencing of amplified C9 cDNA and DNA revealed a nonsense substitution (CGA→TGA) at
codon 95 in exon 4 in the four C9-deficient individuals. An allele-specific polymerase chain reaction system designed to detect
exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation
in exon 4 and that the parents of patient 2 were heterozygous. The common mutation at codon 95 in exon 4 might be responsible
for most Japanese C9 deficiency.
Received: 28 December 1997 / Accepted: 25 February 1998 相似文献
12.
Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe. 总被引:6,自引:0,他引:6
B Dworniczak C Aulehla-Scholz L Kalaydjieva K Bartholomé K Grudda J Horst 《Genomics》1991,11(2):242-246
We report a mutation within the phenylalanine hydroxylase (PAH) gene that causes aberrant splicing of the mRNA and that is in tight association with chromosomal haplotypes 6, 10, and 36. Because of the high frequency of these particular haplotypes in Bulgaria, Italy, and Turkey, it appears to be one of the more frequent defects in the PAH gene causing classical phenylketonuria in this part of Europe. The mutation is a G to A transition at position 546 in intron 10 of the PAH gene, 11 bp upstream from the intron 10/exon 11 boundary. It activates a cryptic splice site and results in an in-frame insertion of 9 nucleotides between exon 10 and exon 11 of the processed mRNA. Normal amounts of liver PAH protein are present in homozygous patients, but no catalytic activity can be detected. This loss of enzyme activity is probably caused by conformational changes resulting from the insertion of three additional amino acids (Gly-Leu-Gln) between the normal sequences encoded by exon 10 and exon 11. 相似文献
13.
Wolf B 《The Journal of nutritional biochemistry》2005,16(7):441-445
Renewed interest in biotinidase, the enzyme responsible for recycling the vitamin biotin, initially came from the discovery of biotinidase deficiency in 1982. Since then, the elucidation of other activities of the enzyme, alternative splicing of the biotinidase gene and differential subcellular localization of the enzyme have prompted speculation and investigations of its other possible functions. The results of these studies have implicated biotinidase in aspects of biotin metabolism, specifically the biotinylation of various proteins, such as histones. Biotinidase may have an important regulatory role(s) in chromatin/DNA function. 相似文献
14.
Deletion polymorphism in the gene for angiotensin converting enzyme is associated with elevated fasting blood glucose levels 总被引:4,自引:0,他引:4
Adriana Zingone Andrea Dominijanni Evelina Mele Onorina Marasco Franca Melina Pasquale Minchella Barbara Quaresima Maria Teresa Tiano Agostino Gnasso Arturo Pujia Nicola Perrotti 《Human genetics》1994,94(2):207-209
The frequency and distribution of angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism, and its association with other known risk factors for coronary atherosclerosis, has been studied, in a normal south Italian population. Subjects homozygous for deletion showed elevated fasting blood glucose levels when compared with subjects homozygous for insertion. The difference was consistent with an increased number of type 2 diabetics among the former group of subjects.Recipient of a post-doctoral fellowship from the Associazione Italiana Ricerca sul Cancro (A.I.R.C.) 相似文献
15.
A common point mutation in the tyrosine hydroxylase gene in autosomal recessive L-DOPA-responsive dystonia in the Dutch population 总被引:4,自引:0,他引:4
L. P. W. J. van den Heuvel Bernadette Luiten J. A. M. Smeitink Johanneke F. de Rijk-van Andel Keith Hyland Gerry C. H. Steenbergen-Spanjers R. J. T. Janssen R. A. Wevers 《Human genetics》1998,102(6):644-646
This report concerns one new mutation in the tyrosine hydroxylase (TH) gene in three patients originating from three unrelated
Dutch families with autosomal recessive L-DOPA-responsive dystonia (DRD). In this study, all exons of the TH gene were amplified
by the polymerase chain reaction and subjected to analyses by single-strand conformation polymorphism. An aberrant migration
pattern was observed for exon 6 of the TH gene in all patients. Direct sequencing of the coding region of exon 6 revealed
the presence of one novel missense mutation. An a698g transition resulted in the substitution of the evolutionary conserved
arginine 233 by a histidine (R233H). All patients were homozygous for the mutation. This new mutation in the TH gene was confirmed
by restriction enzyme analysis with the restriction enzyme HhaI. Thus, a high proportion of defective TH alleles may be R233H in The Netherlands.
Received: 25 July 1997 / Accepted: 10 February 1998 相似文献
16.
Samia Boulechfar Vasco Da Silva Jean-Charles Deybach Yves Nordmann Bernard Grandchamp Hubert de Verneuil 《Human genetics》1992,88(3):320-324
Summary Congenital erythropoietic porphyria (CEP) or Günther's disease is an inborn error of heme biosynthesis transmitted as an autosomal recessive trait and characterized by a profound deficiency of uroporphyrinogen III synthase (UROIIIS) activity. We have previously described two missense mutations in the UROIIIS gene, confirming that the primary defect responsible for CEP is a structural alteration of this gene. We have extended our work to 5 additional unrelated families. Two new point mutations, a deletion and an insertion have been found in the messenger RNA. Our study shows that a molecular heterogeneity of the mutations exists in Günther's disease. One mutation (C73R), however, appears to be more frequent than the others. Finally, the different normal and mutated proteins have been expressed in Escherichia coli to determine the consequence of the mutations on the enzyme activity. 相似文献
17.
A Biason F Mantero C Scaroni E R Simpson M R Waterman 《Molecular endocrinology (Baltimore, Md.)》1991,5(12):2037-2045
The molecular basis of 17 alpha-hydroxylase/17,20-lyase deficiency syndrome in a 14-yr-old 46,XY Italian patient was investigated by amplification, subcloning, and sequencing of specific exonic sequences from genomic DNA samples. A homozygous mutation, consisting of a 518-basepair (bp) deletion combined with a 469-bp insertion, was identified in the CYP17 gene of the patient. The deletion spans much of exon II, the whole intron 2, and a portion of exon III. A part (156 bp) of the inserted sequence shows 95.5% identity to the nuclear antigen-binding site on Marek disease virus DNA and sequences found in rearranged mitochondrial DNA of rat hepatoma cells. A similar degree of sequence identity (99%) was also found between the above sequences and part of the lac operon of E. coli. The inserted sequence is lacking the BamHI site in intron 2 of CYP17 and contains an in-frame stop codon (TAA). Thus, the mutated gene encodes a truncated nonfunctional steroid hydroxylase, giving rise to symptoms associated with complete combined 17 alpha-hydroxylase/17,20-lyase deficiency. The family history revealed that the patient is the child of a consanguineous marriage and has two genotypically and phenotypically female sisters also suffering from symptoms of the disease. Investigation of genomic DNA from these sisters revealed that in each case both CYP17 alleles contained the same mutation. On the other hand, the parents were found to be heterozygous for this mutation. The insertion could not be found in DNA from normal individuals or in the CYP17 gene of other Italian patients with the 17 alpha-hydroxylase deficiency syndrome.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
18.
Naokazu Inoue Toshiyuki Saito Riako Masuda Yoshio Suzuki Michiko Ohtomi H. Sakiyama 《Human genetics》1998,103(4):415-418
The complement system plays an important role in defense mechanisms by promoting the adherence of microorganisms to phagocytic
cells and lysis of foreign organisms. Deficiencies of the first complement components, C1r/C1s, often cause systemic lupus
erythema-tosus-like syndromes and severe pyogenic infections. Up to now no genetic analysis of the C1r/C1s deficiencies has
been carried out. In the present work, we report the first genetic analysis of selective C1s deficiency, the patient having
a normal amount of C1r. C1s RNA with a normal size was detected in patient’s subcutaneous fibroblasts (YKF) by RNA blot analysis
and RT-PCR. The amount of C1s RNA was approximately one-tenth of the RNA from the human chondrosarcoma cell line, HCS2/8.
In contrast, the levels of C1r and β-actin RNA of YKF were similar to that of HCS2/8. Sequence analysis of C1s cDNA revealed
a deletion at nucleotides 1087–1090 (TTTG), creating a stop codon (TGA) at position 94 downstream of the mutation site. Direct
sequencing of the gene between the primers designed on intron 9 and exon 10 indicated the presence of the deletion on exon
10 of the gene. Quantitative Southern blot hybridization suggested the mutation was homozygous. The 4-bp deletion on exon
10 was also found in the patient’s heterozygous mother who had normal hemolytic activity.
Received: 6 July 1998 / Accepted: 1 August 1998 相似文献
19.
kitl非编码区突变导致RNA剪切异常的小鼠 总被引:4,自引:0,他引:4
本文主要采用RT-RCR技术从kitl1-bao纯合子和正常C57BL/6(B6)小鼠总RNA中扩增出kitl基因片段,测序后与GenBank(登录号:NM.013598)序列比对,找到mRNA上突变部位。PCR扩增kitl基因组DNA上对应部位进一步测序验证。结果发现kitl1-bao突变纯合子kitl基因mRNA缺少第8号外显子。在基因组DNA上kitl基因第8号内含子第2个碱基由T转换为C,是引起mRNA剪接错误的原因 相似文献
20.
Ann K. Daly Julian B. S. Leathart Jeffrey R. Idle Stephanie J. London 《Human genetics》1995,95(3):337-341
The cytochrome P450 CYP2D6 is a polymorphic enzyme, for which 5%–10% of Caucasians (poor metabolizers) lack activity. The majority of mutations giving rise to the deficiency have now been identified but some individuals show anomalous phenotype-genotype relationships when screened for the common mutant alleles. We have sequenced all nine exons and intron-exon boundaries in a subject who was phenotypically a poor metabolizer but genotypically heterozygous when screened for the common alleles. A single base-pair deletion (T1795) was detected in exon 3 and a base substitution (G2064A) resulting in an amino acid substitution (G212E) in exon 4. The deletion results in premature termination of translation and a truncated protein. In a group of 50 white Americans, the allele frequency for the new mutant allele was 0.01. The new allele explains some cases of anomalous genotype/phenotype relationships for CYP2D6. 相似文献