3' Acceptor splice site mutation in intron 50 leads to mild Duchenne muscular dystrophy phenotype.
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Adolescent↗
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Results for “Splicing mutations”
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Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations.
Mutations in the GLI3 zinc-finger transcription factor gene cause Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS), which are variable but distinct clinical entities. We hypothesized that GLI3 mutations that predict a truncated functional repressor protein cause PHS and that functional haploinsufficiency of GLI3 causes GCPS. To test these hypotheses, we screened patients with PHS and GCPS for GLI3 mutations. The patient group consisted of 135 individuals: 89 patients with GCPS and 46 patients with PHS. We detected 47 pathological mutations (among 60 probands); when these were combined with previously published mutations, two genotype-phenotype correlations were evident. First, GCPS was caused by many types of alterations, including translocations, large deletions, exonic deletions and duplications, small in-frame deletions, and missense, frameshift/nonsense, and splicing mutations. In contrast, PHS was caused only by frameshift/nonsense and splicing mutations. Second, among the frameshift/nonsense mutations, there was a clear genotype-phenotype correlation. Mutations in the first third of the gene (from open reading frame [ORF] nucleotides [nt] 1-1997) caused GCPS, and mutations in the second third of the gene (from ORF nt 1998-3481) caused primarily PHS. Surprisingly, there were 12 mutations in patients with GCPS in the 3' third of the gene (after ORF nt 3481), and no patients with PHS had mutations in this region. These results demonstrate a robust correlation of genotype and phenotype for GLI3 mutations and strongly support the hypothesis that these two allelic disorders have distinct modes of pathogenesis.
Abnormalities, Multiple↗
Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.
Blood relatives of patients with the inherited disease ataxia telangiectasia (A-T) have an increased susceptibility for breast cancer. We therefore looked for sequence alterations of the ATM gene in a large hospital-based series of unselected breast cancer patients. The whole ATM coding sequence was analyzed in genomic DNA samples from a core group of 192 consecutive breast cancer cases to define the spectrum of ATM gene mutations. Common sequence alterations were then screened in the whole series of 1000 breast cancer patients and in 500 random individuals. In the core group, 21 distinct sequence alterations were identified throughout the ATM coding region, and 1 common splicing mutation was uncovered in intron 10. Almost half of the breast cancer patients (46%) were heterozygotes for 1 of 16 different amino acid substitutions, and three patients (1.6%) carried a truncating mutation. These data indicate that approximately 1 in 50 German breast cancer patients is heterozygous for an A-T-causing mutation. In our extended series, the most common A-T mutation 1066-6T-->G was disclosed in 7 of 1000 (0.7%) breast cancer patients. Transcript analyses indicated that the loss of exon 11 in the ATM mRNA was the pathogenic consequence of this splicing mutation, which produced a <10% of full-length ATM mRNA and ATM protein in a homozygous A-T patient. We also found an excess of rare missense substitutions in the breast cancer cohort compared with random individuals (7.9% versus 5.3% of alleles; odds ratio = 1.6; P < 0.01). One missense substitution, S707P in exon 15, was two times more frequent in breast cancer patients (odds ratio = 2.4; 95% confidence interval, 1.0-5.8) and five times more frequent in patients with bilateral disease than in random individuals (P < 0.001). We conclude that a large variety of distinct ATM mutations and variants exist among breast cancer patients, some of which can contribute to the etiology and progression of the malignancy. Screening for frequent A-T mutations such as the 1066-6-->G splice site substitution can be effective to prospectively identify A-T heterozygotes in an unselected cancer patient population.
Adenocarcinoma↗
Compound heterozygous group A xeroderma pigmentosum patient with a novel mutation and an inherited reciprocal translocation.
The severity of neurological abnormalities in Japanese group A xeroderma pigmentosum (XP-A) patients correlates with the sites of non-sense mutation in the XP-A gene. We describe a patient who presented with a more severe photosensitivity and neurological abnormality than those in typical Japanese XP-A patients with a splicing mutation in intron 3. The patient was compound heterozygous for the splicing mutation in intron 3, which resulted in formation of a non-sense codon in exon 4, and a novel non-sense mutation at codon 208 in exon 5, a C to T transition creating a stop codon TAG. Although the combination of these mutations might have been thought to cause only mild neurological signs, the longer truncated XP-A proteins than those of typical XP-A patients may have resulted in severe neurological symptoms. This phenomenon may be explained by a translocation of chromosome (1;10)(q25.3;q22.3) inherited from his father.
Adult↗
A homozygous splice site mutation affecting the intracellular domain of the growth hormone (GH) receptor resulting in Laron syndrome with elevated GH-binding protein.
Laron syndrome (LS) is a severe autosomal recessive form of GH resistance resulting from molecular defects in the GH receptor (GHR). Affected individuals have extreme short stature and a typical facial phenotype. The point mutations in the GHR gene identified in this condition have until now been confined to the region encoding the extracellular domain of the receptor. We report here the first homozygous point mutation within the intracellular domain of the GHR in two LS cousins distinguishable from classical LS patients only by the presence of elevated GH-binding protein (GHBP) in their serum. A G to C transversion at the vital - 1 position in the splice donor site of exon 8 disrupts normal splicing, resulting in the complete skipping of exon 8, producing a mutant GHR protein lacking transmembrane and intracellular domains. We predict that this mutant protein would not be anchored in the cell membrane and would be measurable in the circulation as GHBP, hence explaining the phenotype of severe GH resistance combined with elevated circulating GHBP.
Base Sequence↗
Identification of a new splice site mutation (3849 + 1G-->A) in the intron 19 of the CFTR gene.
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Alternative Splicing↗
A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I.
BACKGROUND: Hereditary tyrosinemia type I is an autosomal recessive inborn error of metabolism caused by a deficiency of the enzyme fumarylacetoacetate hydrolase. The disorder clusters in the Saguenay-Lac-St.-Jean area of Quebec. In this region, 1 of 1846 newborns is affected and 1 of every 22 persons is thought to be a carrier. Recently, we identified a splice mutation and two nonsense mutations in the fumarylacetoacetate hydrolase gene in two patients from Quebec with tyrosinemia type I. METHODS: We used allele-specific-oligonucleotide hybridization to examine the frequency of these three candidate mutations in patients with tyrosinemia type I and in the population of Quebec. RESULTS: The splice mutation was found in 100 percent of patients from the Saguenay-Lac-St.-Jean area and in 28 percent of patients from other regions of the world. Of 25 patients from the Saguenay-Lac-St.-Jean region, 20 (80 percent) were homozygous for this mutation, a guanine-to-adenine change in the splice-donor sequence in intron 12 of the gene, indicating that it causes most cases of tyrosinemia type I in the region. The frequency of carrier status, based on screening of blood spots from newborns, was about 1 per 25 in the Saguenay-Lac-St.-Jean population and about 1 per 66 overall in Quebec. CONCLUSIONS: This study identified the most prevalent mutation causing hereditary tyrosinemia in French Canada; it also showed the feasibility of DNA-based testing for carriers in the population at risk.
Alleles↗
A splice site mutation in the gene of the human type I hair keratin hHa1 results in the expression of a tailless keratin isoform.
In this study, we have elucidated the molecular mechanisms underlying the expression of an acidic 41-kDa protein inherited as an autosomal dominant trait of the hair keratin pattern of about 5% of the human population. We show that this protein is a size variant of the large type I hair cortex keratin hHa1 due to a genetic polymorphism in the hHa1 gene. We detected a G-A substitution in the 5' splice site of intron 6 of the hHa1 gene, which segregates with the 41-kDa protein phenotype in two pedigrees and is responsible for the formation of an abnormally spliced hHa1 mRNA species. The use of an alternative 5' splice site leads to the retention of 41 nucleotides of the initial intron 6 sequences in the mature transcript. The open reading frame of the aberrant mRNA creates a premature stop codon immediately downstream of the mutation site. The resulting hHa1 protein variant, hHa1-t, is about 6-kDa smaller than the 47-kDa hHa1 hair keratin and lacks the complete nonhelical tail domain. We show that the tailless hHa1-t is functional, since both recombinant hHa1 and hHa1-t form identical keratin intermediate filaments when assembled in vitro with a type II hair keratin partner. This finding confirms the view of a noninvolvement of the keratin tail domain in filament assembly and explains the lack of a pathological hair phenotype in hHa1-t positive individuals.
Base Sequence↗
Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity.
Thiopurine methyltransferase (TPMT) catalyzes S-methylation of thiopurine drugs such as 6-mercaptopurine. Large variations in levels of TPMT activity in human tissue can result from a common genetic polymorphism with a series of alleles for low activity. This polymorphism is an important factor responsible for large individual variations in thiopurine toxicity and therapeutic efficacy. We now report a new variant allele, TPMT*4, that contains a G--> A transition that disrupts the intron/exon acceptor splice junction at the final 3' nucleotide of intron 9, the terminal intron of the TPMT gene. This new allele cosegregated within an extended kindred with reduced TPMT activity. We attempted to determine the mechanism(s) by which the presence of TPMT*4 might result in low enzyme activity. Although very few mature transcripts derived from allele TPMT*4 were detected, the mutation did lead to generation of at least two aberrant mRNA species. The first resulted from use of a novel splice site located one nucleotide 3' downstream from the original splice junction. That mRNA species contained a single nucleotide deletion and a frameshift within exon 10, the terminal exon of the gene. The second novel mRNA species resulted from activation of a cryptic splice site located within intron 9, leading to inclusion of 330 nucleotides of intron sequence. That sequence contained a premature translation termination codon. TPMT*4 is the first reported allele for low TPMT activity as a result of a mutation within an intron. These observations also provide insight into mechanisms of mRNA processing after disruption of a terminal exon splice junction.
Adenine↗
A rare homozygous rhodopsin splice-site mutation: the issue of when and whether to offer presymptomatic testing.
Having identified a disease-associated rhodopsin mutation in a patient with retinitis pigmentosa (RP), the issue is to address the question of whether to offer genetic testing to at-risk family members. Two members of a South African (SA) family, one of whom suffers from RP, as well as 54 unrelated SA RP patients from the same population group were investigated using single-stranded conformational polymorphism analysis followed by DNA sequencing. A rare homozygous mutation at the intron-exon boundary of exon 4 in the rhodopsin gene was identified in the proband. One of his siblings was found to be heterozygous for the same mutation. The mutation was not detected in the 54 unrelated SA RP patients examined, 11 of whom were sporadic cases. A low incidence of RP amongst heterozygous carriers of this mutation has been reported; however, in the past it has been unclear whether the mutation has an effect in single copy or dual copy. To the best of our knowledge, this is the first time that this mutation has been reported as homozygous in an affected individual, thereby resolving the issue and confirming that it is a recessive disease-associated mutation. This is also the first autosomal recessive RP disease-causing rhodopsin mutation that has been identified in Southern Africa. Analysis of the extended pedigree indicated obligate heterozygous carriers of the mutation, without obvious signs of visual impairment in early adulthood. The extent to which potential heterozygous carriers should be pursued and clinically examined is discussed and the question is addressed as to whether to inform the family of these molecular findings.
Aged↗
Characterization of an intron 31 splice junction mutation in the neurofibromatosis type 1 (NF1) gene.
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Adolescent↗
Echo of silence: silent mutations, RNA splicing, and neuromuscular diseases.
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Alternative Splicing↗
Genetic basis of dominantly inherited transient bullous dermolysis of the newborn: a splice site mutation in the type VII collagen gene.
Transient bullous dermolysis of the newborn (TBDN) is a blistering disease evident at birth or shortly thereafter, but the blistering tendency decreases with advancing age. The tissue separation in TBDN is below the lamina densa, and electron microscopy has revealed abnormalities in anchoring fibrils. Immunofluorescence staining demonstrates intracellular accumulation of type VII collagen. In this study, we report a G-to-C transversion mutation in the last nucleotide of intron 35 of the type VII collagen gene (COL7A1) in a family with autosomal dominant TBDN in three generations. This nucleotide substitution abolishes the obligatory consensus 3'-acceptor splice site, predicting in-frame skipping of exon 36. Thus, TBDN in this family is caused by a mutation in COL7A1, and is therefore allelic with other variants of dominant dystrophic epidermolysis bullosa.
Child, Preschool↗
A novel splicing junction mutation in the gene for the steroidogenic acute regulatory protein causes congenital lipoid adrenal hyperplasia.
Congenital lipoid adrenal hyperplasia (lipoid CAH) is a relatively common genetic disorder of adrenal and gonadal steroidogenesis and is the most severe form of CAH. As typical affected individuals cannot produce any steroid hormones or can only produce low levels of steroid hormones in the adrenals and gonads, including glucocorticoids, mineralcorticoids, and sex steroids, a genetic defect in the cholesterol side-chain cleavage enzyme, cytochrome P450scc (CYPXIA1), has been postulated to be the cause of their insufficient production to date. Recently, Lin and co-workers proved a link between mutations of the steroidogenic acute regulatory protein (StAR) gene and the lipoid CAH phenotype. Therefore, we investigated both the cytochrome P450scc and StAR genes in a Korean family with a fairly mild form of lipoid CAH to identify the mutation(s) causing this disease. The result was that no mutations could be found in the two genes, except for a thymine (T) insertion into intron 2 of the StAR gene, 3 bp from the splice donor site of exon 2. PCR-amplified StAR genes from a normal subject and the patient were cloned into an expression vector and then introduced into COS-7 cells. Northern blot and reverse transcriptase-PCR analyses indicated that the StAR messenger ribonucleic acid derived from the vector with the normal StAR gene spliced exons 2 and 3 correctly, whereas most, but not all, StAR messenger ribonucleic acid derived from the vector with the T-inserted StAR gene could not remove intron 2. We concluded from these results that the T insertion into the StAR gene accounts for the lipoid CAH phenotype in this patient.
Adrenal Hyperplasia, Congenital↗
Splice site mutation causing a seven amino acid Notch3 in-frame deletion in CADASIL.
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Alleles↗
Intron mutations affect splicing of Saccharomyces cerevisiae SUP53 precursor tRNA.
The Saccharomyces cerevisiae amber suppressor tRNA gene SUP53 (a tRNALeu3 allele) was used to investigate the role of intron structure and sequence on precursor tRNA splicing in vivo and in vitro. This gene encodes a pre-tRNA which contains a 32-base intervening sequence. Two types of SUP53 intron mutants were constructed: ones with an internal deletion of the natural SUP53 intron and ones with a novel intron. These mutant genes were transcribed in vitro, and the end-processed transcripts were analyzed for their ability to serve as substrates for the partially purified S. cerevisiae tRNA endonuclease and ligase. The in vitro phenotype of these mutant RNAs was correlated with the in vivo suppressor tRNA function of these SUP53 alleles after integration of the genes into the yeast genome. Analysis of these mutant pre-tRNAs, which exhibited no perturbation of the mature domain, clearly showed that intron structure and sequence can have profound effects on pre-tRNA splicing. All of the mutant RNAs, which were inefficiently spliced or unspliced, evidenced cleavage only at the 5' splice junction. Base changes in the intron proximal to the 3' splice junction could partially rescue the splicing defect. The implications of these data for tRNA endonuclease-substrate interactions are discussed.
Computer Simulation↗
The human T-cell transcription factor-4 gene: structure, extensive characterization of alternative splicings, and mutational analysis in colorectal cancer cell lines.
The human T cell transcription factor-4 (hTCF-4) interacts functionally with beta-catenin in the Wnt signaling pathway, which regulates many developmental processes. Moreover, inappropriate reactivation of this pathway attributable to APC or beta-catenin mutations has been described in colorectal cancers. Because only the human TCF-4 cDNA sequence was known, we determined its genomic structure. A total of 17 exons, of which 5 were alternative, were identified. Moreover, four alternative splice sites were observed either experimentally or in silico by a BLAST approach in expressed sequence tag databases. The alternative use of three consecutive exons localized in the 3' part of the hTCF-4 gene changes the reading frames used in the last exon, leading to the synthesis of a number of hTCF-4 isoforms with short, medium, or long-size COOH-terminal ends. We next screened the entire hTCF-4 gene for mutations in a series of 24 colorectal cancer cell lines by denaturing gradient gel electrophoresis and/or direct sequencing. Besides an already described deletion of an A in an (A)9 coding repeat in four cases, we found DNA variants in eight cases for a total of 12 variants, of which 8 were coding. These include one frameshift mutation in the beta-catenin binding domain (exon 1), and one missense mutation in exon 4. In the remaining six cases, nonsense or frameshift mutations were localized in the 3' part of the gene. These latter alterations have as a common consequence to decrease the proportion of the long COOH-terminal hTCF-4 isoform, which contains two binding domains for c-terminal binding protein, a protein implicated in the repression of the TCF family transcriptional activity. Thus, loss of the TCF-4 capacity to interact with COOH-terminal binding protein could be an important event during colorectal carcinogenesis by modifying Wnt signaling.
Alternative Splicing↗
A splice site mutation of alpha-spectrin gene causing skipping of exon 18 in hereditary elliptocytosis.
Spectrin Oran (alpha II/21) has been reported previously as a variant of the alpha II domain. Its expression level is low (10% of total spectrin) in heterozygotes denoting a major disadvantage of the mutated alpha-chain dimer or tetramer with respect to their normal counterparts. Spectrin Oran is associated with symptomatic elliptocytosis in the homozygous state. A 1-minute digestion time allowed to perceive a fast trypsin cleavage (not existing normally) after Arg 890 (helix 3 of repeating segment alpha 9). The responsible change was the lack of amino acids 822 to 862 (helix 2 of repeating segment alpha 8). Such a situation fits with the phasing of spectrin according to which mutated helix 2 and distorted helix 3 are adjacent to one another. The internal position of the structural change accounts for the slight self-association defect. The ultimate genetic lesion was a G to A substitution (intronic position-1) in the acceptor splice site of intron 17 resulting in skipping of exon 18. The substitution also created an acceptor splice site 1 base downstream, but the latter was used at a low grade.
Alleles↗