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Results for “Splicing mutations”

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At least 199 records · Page 11Linked to original sources
PubMed1995

A novel splicing mutation in propionic acidemia associated with a tetranucleotide direct repeat in the PCCB gene.

Propionic acidemia is an inborn error of organic acid metabolism caused by a deficiency of propionyl Coenzyme A (CoA) carboxylase. cDNAs sequenced from a beta subunit deficient Japanese patient (no. 187) showed an in-frame 57-bp deletion in one allele. Genomic DNA analysis revealed a four-nucleotide deletion of bases 3 to 6 in the 3' intron adjacent to the deleted exon, which disrupted the consensus 5' splice signal and caused exon skipping. This deletion removed one-half of a tetranucleotide direct repeat at the splice junction and presumably resulted from slipped mispairing.

Acyl Coenzyme A↗
PubMed2005

A splicing mutation in the alpha/beta GlcNAc-1-phosphotransferase gene results in an adult onset form of mucolipidosis III associated with sensory neuropathy and cardiomyopathy.

A 47-year-old female who presented with a dilated cardiomyopathy and mild neuropathy was found to have pseudoHurler polydystrophy (mucolipidosis III). The serum lysosomal enzymes were strikingly elevated and GlcNAc-1-phosphotransferase activity in the patient's fibroblasts was 3% of normal. Sequence analysis of the patient's genomic DNA revealed a homozygous mutation of the last nucleotide of the 135-bp exon 7 of the phosphotransferase gene encoding the alpha/beta subunits, resulting in aberrant splicing and skipping of this exon. Remarkably, none of the skeletal and connective tissue anomalies characteristic of the disease were present. This case is the first example of mucolipidosis III presenting in an adult patient and further broadens the clinical spectrum of the disease.

Age of Onset↗
PubMed1995

Leaky splicing mutation in the acid maltase gene is associated with delayed onset of glycogenosis type II.

An autosomal recessive deficiency of acid alpha-glucosidase (GAA), type II glycogenosis, is genetically and clinically heterogeneous. The discovery of an enzyme-inactivating genomic deletion of exon 18 in three unrelated genetic compound patients--two infants and an adult--provided a rare opportunity to analyze the effect of the second mutation in patients who displayed dramatically different phenotypes. A deletion of Lys-903 in one patient and a substitution of Arg for Leu-299 in another resulted in the fatal infantile form. In the adult, a T-to-G base change at position -13 of intron 1 resulted in alternatively spliced transcripts with deletion of exon 2, the location of the start codon. The low level of active enzyme (12% of normal) generated from the leakage of normally spliced mRNA sustained the patient to adult life.

Adult↗
PubMed1993

Overexpression of a truncated growth hormone receptor in the sex-linked dwarf chicken: evidence for a splice mutation.

Sex-linked dwarfism in chickens is a form of GH resistance that resembles the Laron syndrome in humans. The dwarfism found in chickens is due to a mutant gene (dw) carried on the sex chromosome. The homozygous dwarf (dwdw) chicken is characterized by reductions in stature and plasma insulin-like growth factor-I (IGF-I) levels. Despite the absence of hepatic GH-binding activity, Southern blot analysis shows that there is no gross structural change in the gene for the GH receptor (GHR) in this strain of dwdw chicken. GH-dependent IGF-I production can be restored in cultured dwdw hepatocytes after transfection and transient expression of a chicken GHR (cGHR) cDNA, indicating that other factors that participate in GH-mediated IGF-I synthesis are intact. Northern blot analysis of liver, muscle, fat, and pituitary RNA from normal (DwDw) chickens shows a major transcript of 4.3 kilobases (kb) and three minor transcripts (0.8, 1.7, and 3.2 kb), which correspond to the cGHR. In contrast, the 0.8-kb transcript is the major cGHR transcript expressed in these tissues from dwdw chickens. Northern blot analysis with domain-specific probes shows that the 0.8-kb transcript in DwDw and dwdw liver contains only a small portion of the extracellular domain of the cGHR. A cDNA clone encoding this transcript has been isolated from a liver library prepared from a normal chicken.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2006

crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1).

We describe a novel spontaneous autosomal recessive mutation, cervelet-4 (crv4), which arose in a BALB/c strain. Mice homozygous for the mutation exhibit principally a reduced body size, a congenital neurological phenotype characterized by ataxic gait and intention tremor, with no gross anomalies observed in brain or cerebellum, and skeletal anomalies. Using linkage analysis, we mapped the crv4 locus to the proximal region of chromosome 10, at the location of the Grm1 gene. Genetic complementation crosses between crv4 and Grm1 KO mice confirmed that crv4 is a new allele of Grm1. Molecular analysis of the Grm1 gene in mutant mice revealed the insertion of a 190-bp LTR fragment in intron 4. Our results also indicated that the presence of the LTR fragment caused the disruption of the Grm1 normal splicing process and complete absence of the wild-type protein. crv4 is an interesting model to extend the study of Grm1 function and the pathological effects of Grm1 deficiency in vivo.

Animals↗
PubMed1998

Autosomal dominant zonular cataract with sutural opacities is associated with a splice mutation in the betaA3/A1-crystallin gene.

PURPOSE: Congenital cataracts constitute a morphologically and genetically heterogeneous group of diseases that are a major cause of childhood blindness. Autosomal Dominant Zonular Cataracts with Sutural Opacities (CCZS) have been mapped to chromosome 17q11-q12 near the betaA3A1-crystallin gene (CRYBA1). The betaA3A1-crystallin gene was investigated as the causative gene for the cataracts. METHODS: The betaA3/A1-crystallin gene was sequenced in affected and control individuals. Base changes were confirmed and assayed in additional family members and controls using NlaIII restriction digestion of PCR amplified DNA sequences. Base changes were assessed for their effects on splicing by information analysis. RESULTS: The cataracts are associated with a sequence change in the 5' (donor) splice site of intron 3: GC(g->a)tgagt. The sequence change also creates a new NlaIII site. This base change cosegregates with the cataracts in this family, being present in every affected individual. Conversely, this base change was not seen in 140 chromosomes examined in 70 unaffected and unrelated individuals. Information theory mutational analysis shows that the base change lowers the information content of the splice site from 6.0 to -6.8 bits, so that splicing would not be expected to occur at the altered site. CONCLUSIONS: Taken together, these observations suggest that the observed mutation might be causally related to the cataracts in this family.

Amino Acid Sequence↗
PubMed2002

A novel splicing mutation causes an undescribed type of analbuminemia.

Analbuminemia is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous subjects. In this report we describe a new molecular defect that caused the analbuminemic trait in a newborn of Iraqi origin. When the parents' DNA was analyzed, both subjects were found to be heterozygous for the same mutation found in the infant. All the 14 exon and flanking intron sequences of the albumin gene were amplified via PCR and screened for mutations by SSCP and heteroduplex analysis. A mutation in the DNA region encoding exon 1 and its flanking intron was revealed by the presence of a heteroduplex. The fragment, which was directly DNA sequenced, contains a previously unreported single nucleotide change, consisting in a G to A substitution at nucleotide 118 in the structural gene of the human protein. This mutation, involving the first base of intron 1, destroys the GT dinucleotide consensus sequence found at the 5' end of most intervening sequences and causes the defective pre-mRNA splicing responsible for the analbuminemic trait.

Adult↗
PubMed1992

An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds.

Sandhoff disease is caused by mutations affecting the beta subunit of lysosomal beta-hexosaminidase (EC 3.2.1.52) and displays a wide spectrum of clinical phenotypes. We report a 57-year-old patient with a very mild phenotype, although residual hexosaminidase A activity in his cultured fibroblasts was less than 3% of normal activity, a level observed in juvenile onset patients. Northern and Western blot analyses confirmed a similar low level of beta subunit-mRNA and mature beta-protein, respectively. Two mutations of the HEXB gene were identified in this patient, a partial 5' gene deletion (a null allele), and a C----T transition 8 nucleotides downstream from the intron 10/exon 11 junction affecting the splicing of the beta subunit-mRNA. In their homozygous forms, the 5' deletion has been previously shown to result in a severe infantile phenotype, and the C----T transition in a juvenile phenotype. The genotype and the low level of residual hexosaminidase A activity would be expected to produce a juvenile Sandhoff phenotype in this patient, as well as in four of his six clinically normal siblings. The biochemical basis of his mild phenotype is uncertain, but may result from genetic variations in the RNA splicing machinery.

Base Sequence↗
PubMed1998

Donor splice mutation (665 + 1 G_T) in familial hypobetalipoproteinemia with no detectable apoB truncation.

We report a 49-member four-generation kindred in which 11 members express familial hypobetalipoproteinemia (FHBL). In other kindreds, various truncated apoB species cosegregate with the FHBL phenotype. In contrast, no truncated apoB proteins were found by immunoblotting of plasma samples in this kindred. Previous linkage analysis showed strong linkage of FHBL to apoB markers. Nucleotide sequence analysis demonstrated a 665 + 1 G_T transition in the splice donor site of intron 5. This probably alters the accuracy and efficiency of mRNA splicing leading to the extremely low apoB levels in plasma. In addition, we detected four novel polymorphisms in the apoB gene.

Adolescent↗
PubMed1995

Splicing mutations of the polycystic kidney disease 1 (PKD1) gene induced by intronic deletion.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disease which frequently results in renal failure. The major ADPKD gene, polycystic kidney disease 1 (PKD1), has recently been identified. In an attempt to understand better the aetiology of this disorder we have searched for mutations in the PKD1 gene. Analysis of three regions in the 3' part of the gene has revealed two mutations that occur by a novel mechanism. Both mutations are deletions (of 18 or 20 bp) within the same 75 bp intron and although these deletions do not disrupt the splice donor or acceptor sites at the boundary of the intron, they nevertheless result in aberrant splicing. Two different transcripts are produced in each case; one includes the deleted intron while the other has a 66 bp deletion due to activation of a cryptic 5' splice site. No normal product is generated from the deleted gene. Aberrant splicing probably occurs because the deleted intron is too small for spliceosome assembly using the authentic splice sites; this mechanism has previously only been described from in vitro studies of vertebrate genes. A 9 bp direct repeat has been identified within the intron, which probably facilitated deletion by promoting misalignment of sequence. The possible phenotypic implications of producing more than one aberrant PKD1 transcript in these cases are discussed.

Adult↗