Homozygosity for a splice site mutation of the COL1A2 gene yields a non-functional pro(alpha)2(I) chain and an EDS/OI clinical phenotype.
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Alternative Splicing↗
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Results for “Splicing mutations”
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Mutations of the retinal specific ATP binding transporter gene (ABCR) in a single family segregating both autosomal recessive retinitis pigmentosa RP19 and Stargardt disease: evidence of clinical heterogeneity at this locus.
Stargardt disease (STGD) is an autosomal recessive macular dystrophy of childhood characterised by bilateral loss of central vision over a period of several months. STGD has been mapped to chromosome 1p22.1 and recently ascribed to mutations in the retinal specific ATP binding transporter gene (ABCR). The fundus flavimaculatus with macular dystrophy (FFM), an autosomal recessive condition responsible for gradual loss of visual acuity in adulthood (second to third decade) has also been mapped to the same locus. However, a gene for autosomal recessive retinitis pigmentosa with distinctive features of choriocapillaris atrophy at an advanced stage (RP19) has been mapped to the genetic interval encompassing the STGD gene on chromosome 1p (D1S435-D1S236), raising the question of whether, despite striking differences in clinical course and presentation, RP19 and STGD might be allelic disorders at the ABCR locus. In a family segregating RP and STGD in two first cousins, we found that heterozygosity for a splicing mutation in the ABCR gene (1938-1 G-->A) resulted in STGD while hemizygosity for this splice mutation resulted in RP, and when studying the RP patient's parents, we found a maternal non-contribution with apparent segregation of a null allele ascribed to a partial deletion of the ABCR gene. The present study shows that, despite striking clinical differences, RP19 and STGD are allelic disorders at the ABCR locus.
ATP-Binding Cassette Transporters↗
Linkage disequilibrium between mutation and RFLP haplotype at the phenylalanine hydroxylase locus in the German population.
Restriction fragment length polymorphism (RFLP) haplotypes at the phenylalanine hydroxylase (PAH) locus have been determined in 60 German families with PAH deficiency. Similar to the Danish population, about 90% of the mutant alleles are confined to four distinct haplotypes. There are however, differences in the frequency distribution of these haplotypes among the mutant alleles between the two populations. Using an oligonucleotide probe for the splicing mutation associated with mutant haplotype 3 in the Danish population, a tight association between the mutation and the RFLP haplotype has also been observed in Germany. The results provide strong evidence that the splicing mutation occurred on a haplotype 3 chromosome and that the mutant allele has spread into different populations among Caucasians.
Adult↗
Identification of a 3' acceptor splice site mutation (g2610c) in the acid sphingomyelinase gene of patients with Niemann-Pick disease.
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Base Sequence↗
Splice site mutation causing deletion of exon 21 sequences from the pro alpha 2(I) chain of type I collagen in a patient with severe dentinogenesis imperfecta but very mild osteogenesis imperfecta.
An eight-year-old boy was referred for dental assessment of dentinogenesis imperfecta, a full clinical examination also revealed joint hypermobility and some features of mild osteogenesis imperfecta although he had suffered few fractures. Analysis of the collagens produced by both gingival and skin fibroblast cultures showed the synthesis and intracellular retention of an abnormal alpha 2(I) chain that migrated faster than normal on SDS-PAGE. Cyanogen bromide peptide mapping of this intracellular protein indicated a probable deletion in the N-terminal peptide alpha 2CB4. The denaturation temperature of the mutant protein was only 36 degrees C, some 6 degrees C below normal. At 37 degrees C secretion of abnormal protein was not detectable but a lower temperature (30 degrees C) some was secreted into the medium. RT-PCR amplification of mRNA coding for alpha 2CB4 revealed a heterozygous deletion of the 108 bp exon 21 of COL1A2. Sequencing of PCR amplified genomic DNA identified a G --> A transition in the moderately conserved + 5 position of the IVS 21 5' consensus splice site causing the skipping of exon 21. Hybridization with allele-specific oligonucleotides showed no other family member had this base change. Since the cDNA deletion was associated with the (-) allele of a Pvu II polymorphism in exon 25 of COL1A2 we could demonstrate that the mutant pre-mRNA was alternatively spliced yielding both full length and deleted transcripts. Family genotype analysis indicated the mutation had originated in the paternal alpha 2(I) gene.
Alternative Splicing↗
Alternative splicing and mutation status of CHEK2 in stage III breast cancer.
The DNA damage checkpoint kinase, CHK2, promotes growth arrest or apoptosis through phosphorylating targets such as Cdc25A, Cdc25C, BRCA1, and p53. Both germline and somatic loss-of-function CHEK2 mutations occur in human tumours, the former linked to the Li-Fraumeni syndrome, and the latter found in diverse types of sporadic malignancies. Here we examined the status of CHK2 by genetic and immunohistochemical analyses in 53 breast carcinomas previously characterized for TP53 status. We identified two CHEK2 mutants, 470T>C (Ile157Thr), and a novel mutation, 1368insA leading to a premature stop codon in exon 13. The truncated protein encoded by CHEK2 carrying the 1368insA was stable yet mislocalized to the cytoplasm in tumour sections and when ectopically expressed in cultured cells. Unexpectedly, we found CHEK2 to be subject to extensive alternative splicing, with some 90 splice variants detected in our tumour series. While all cancers expressed normal-length CHEK2 mRNA together with the spliced transcripts, we demonstrate and/or predict some of these splice variants to lack CHK2 function and/or localize aberrantly. We conclude that cytoplasmic sequestration may represent a novel mechanism to disable CHK2, and propose to further explore the significance of the complex splicing patterns of this tumour suppressor gene in oncogenesis.
Alternative Splicing↗
A new case of frontotemporal dementia and parkinsonism resulting from an intron 10 +3-splice site mutation in the tau gene: clinical and pathological features.
Hereditary frontotemporal dementia and parkinsonism (FTDP) linked to chromosome 17 (FTDP-17) constitutes a new form of tauopathy, and mutations in the tau gene have recently been reported in some affected families. This report presents clinical and neuropathological data from a member of a British family (SOT 254) with a history of dementia and movement disorder. The medical history of the affected patient, a woman aged 44 years, was reviewed, and a detailed post-mortem examination of the brain was undertaken. A panel of well characterized phosphorylation-dependent and independent anti-tau antibodies was used to assess tau pathology, and inclusions were examined by electron microscopy. Neuronal loss and gliosis were widely distributed, but most severe in neocortical regions, and were associated with abundant neuronal and glial tau inclusions which consisted of a mixture of paired helical filaments (PHFs), similar to those in Alzheimer's disease, and distinct twisted ribbon-like filaments. Genomic DNA was obtained from post-mortem tissue from the index patient, and blood from two unaffected members of the same family. For the index case only, sequencing of intronic sequences flanking exon 10 of the tau gene identified a G to A transition at position +3 of the splice-donor site downstream of exon 10, identical to that reported in multiple system tauopathy with presenile dementia (MSTD). The clinical, neuropathological and genetic findings strongly suggest that SOT 254 represents a new example of FTDP-17 resulting from a mutation in the tau gene. These results are compared with those reported for other FTDP-17 families, i.e. for MSTD.
Adult↗
Temperature sensitivity of aberrant RNA splicing with a mutation in the G+5 position of intron 37 of the gene for type III procollagen from a patient with Ehlers-Danlos syndrome type IV.
A single-base mutation in intron 37 of the gene for type III procollagen (COL3A1) was found in a proband with the type IV variant of Ehlers-Danlos syndrome. Probe-protection experiments with S1 nuclease and RNA from fibroblasts incubated at 37 degrees C demonstrated that about 35% of the total mRNA or about 70% of the mRNA from mutated allele was spliced by exon skipping. The effects of the mutation were temperature-sensitive in that the amount of RNA from the mutated allele that was spliced by exon skipping was 87.1 +/- 7.7% at 31 degrees C, 70.1 +/- 6.5% at 37 degrees C, and 85.4 +/- 11.1% at 42 degrees C. The effects of temperature on aberrant RNA splicing were, therefore, the reverse of those reported for four previous mutants in collagen genes. The increase in abnormal RNA splicing when the temperature was raised from 31 degrees to 37 degrees C seen with previously reported mutants suggested that RNA-RNA hybridization of U1snRNA to the 5'-splice site in the substrate may be limiting in the processing of transcripts from the mutated alleles, since RNA-RNA hybridizations become less favorable at higher temperatures. The decrease in abnormal RNA splicing seen here when the temperature was raised from 31 degrees to 37 degrees C suggested that protein-RNA or protein-protein binding steps become rate limiting with the G+5 mutation in intron 37 of the COL3A1 gene.
Adolescent↗
Identification of a novel splice-site mutation of the BRCA1 gene in two breast cancer families: screening reveals low frequency in Icelandic breast cancer patients.
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Alleles↗
Two novel mutant alleles of the gene encoding neurotrophic tyrosine kinase receptor type 1 (NTRK1) in a patient with congenital insensitivity to pain with anhidrosis: a splice junction mutation in intron 5 and cluster of four mutations in exon 15.
Congenital insensitivity to pain with anhidrosis (CIPA), also called hereditary sensory and autonomic neuropathy type IV (HSAN IV), is caused by mutations of the NTRK1 gene coding for the neurotrophic tyrosine kinase receptor type 1. We report the results of the NTRK1 sequence analysis in a CIPA family from Poland. We found that the patient was in a state of compound heterozygosity. He had one mutant allele with a novel G>A substitution in the conserved splice junction donor site affecting the first base pair of intron 5 (IVS5+1G>A). In the other allele he had a cluster of four single nucleotide substitutions in exon 15: an 1876C>T change (relative to the transcription start site) and three G>T changes (1904G>T, 1909G>T and 1915G>T). All of these mutations change the sense of the codons: H598Y, G607V, E609X and V611L, respectively. Mutations E609X and V611L are novel and unique to the patient family and at least one of them, which creates a premature stop codon in position 609, should have a deleterious effect on the gene function. The other two substitutions H598Y and G607V are most likely rare polymorphisms, which are in linkage disequilibrium. They occur together with an estimated allele frequency of about 6%. Our report increases the spectrum of NTRK1 mutations in CIPA patients and describes an unusual case of a cluster of four mutations located close to each other in one exon.
Alleles↗
WT1 splice site mutation in a 46,XX female with minimal-change nephrotic syndrome and Wilms' tumour.
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Alternative Splicing↗
A splice-junction mutation responsible for familial apolipoprotein A-II deficiency.
The first case of familial apolipoprotein A-II (apo A-II) deficiency was recently reported from Hiroshima, Japan, and designated apo A-IIHiroshima. The proband had no immunologically detectable apo A-II in her plasma. DNA sequence analysis showed that the proband was homozygous for a G----A transition at position 1 of intron 3 of the apo A-II gene. A sister of the proband, who had an intermediate level of plasma apo AII, was shown to be heterozygous for this base substitution. This splice-junction alteration is most likely responsible for apo A-II deficiency, since it would be expected to completely block splicing of intron 3 from the primary transcript and therefore prevent formation of functional mRNA. This deficiency seems to have little influence either on lipid and lipoprotein profiles or on the occurrence of coronary artery disease.
Apolipoprotein A-II↗
A new betaA1-crystallin splice junction mutation in autosomal dominant cataract.
PURPOSE: To map the locus for autosomal dominant cataracts (ADCs) in a Brazilian family using candidate gene linkage analyses, describe the clinical variability, and identify potential mutations in the human betaA1-crystallin gene (CRYBA1), a candidate gene identified through linkage studies demonstrating cosegregation with markers on chromosome 17. METHODS: Members of a Brazilian family with ADC were studied. Clinical examinations and linkage analyses with polymerase chain reaction (PCR) polymorphisms of 22 anonymous markers and 2 within the neurofibromatosis type 1 gene were performed; two-point lod scores were calculated. DNA sequences of all 6 exons and 12 exon-intron boundaries of the betaA1-crystallin gene, a proximal candidate gene mapped to 17q11.1-q12 in one unaffected and two affected individuals, were screened and new variants assessed for cosegregation with the disease. RESULTS: Affected individuals exhibited variable expressivity of pulverulent opacities in the embryonal nucleus and sutures; star-shaped, shieldlike, or radial opacities in the posterior embryonal nucleus; and/or midcortical opacities. All known loci for ADC in this family on chromosomes 1 and 13 were excluded. A positive lod score on chromosome 17 was calculated. This ADC locus was mapped to two potential regions on the long arm with an intervening recombination. The only known candidate gene in these regions was betaA1-crystallin. Three previously unreported single nucleotide variants were found in this gene, one in the donor splice junction site of intron C. This variant was found in all affected members and is presumed to be the causative mutation. CONCLUSIONS: An ADC locus was mapped in a Brazilian family with variable expressivity to either 17q23.1-23.2 or 17q11.1-12 based on linkage analyses. Analyses of DNA sequences of the betaA1-crystallin gene in this family revealed three new variants, one of which is within a donor splice junction and cosegregates with affected members.
Base Sequence↗
Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma.
The objective of our study was to determine the frequency of EGF-receptor-gene rearrangement in relation to tumour-growth behaviour in an unselected group of glioma patients. We investigated 73 glial tumours with different grades of malignancy (17 low-grade gliomas, 14 anaplastic variants, and 42 GBM) by Southern analysis, reverse transcriptase PCR (RT-PCR) amplification of mRNA, and Western analysis. An amplification of the EGF-receptor gene was present in 19/42 GBM but in only 1 anaplastic astrocytoma. By RT-PCR, 4/19 GBM with gene amplification showed a specific amino-terminal aberrant splice mutation of 801 bp in addition to undeleted mRNA. By Western analysis, 27/42 GBM showed expression of the EGF-receptor protein. Protein levels, however, varied among individual tumours. Four GBM containing an aberrant splice mutation exhibited an immunoreactive protein of 130 kDa MW in addition to the normal EGF-receptor protein p170. All GBM patients underwent surgery followed by a standard course of radiotherapy. Neuroradiological follow-up in 31/42 GBM patients consisted of bimonthly MRI examinations. There was a statistically significant difference in the mean latency period until tumour regrowth of patients suffering from GBM with and without EGF-receptor-gene amplification (9 weeks vs. 32 weeks). Our data indicate more rapid tumour regrowth kinetics of GBM with amplified EGF receptor genes in vivo.
Adolescent↗
A novel splice donor mutation affecting position +3 in intron 6 of the factor VIII gene.
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Base Sequence↗
Chinese white Rongchang pig does not have the dominant white allele of KIT but has the dominant black allele of MC1R.
The mast/stem cell growth factor receptor (KIT) and melanocortin receptor 1 (MC1R) mutations are responsible for coat color phenotypes in domestic pigs. Rongchang is a Chinese indigenous pig breed with a white coat color phenotype. To investigate the genetic variability of the KIT and MC1R genes and their possible association with the coat color phenotype in this breed, a gene duplication and splice mutation of KIT were diagnosed in a sample of 93 unrelated Rongchang animals. The results show that Rongchang pigs have a single copy of KIT without the splice mutation at the first nucleotide of intron 17, indicating that the dominant white I allele of KIT is not responsible for their white phenotype. The KIT mRNA and MC1R coding sequences were also determined in this breed. Three putative amino acid substitutions were found in the KIT gene between Rongchang and Western white pigs, their association with the Rongchang white phenotype remains unknown. For the MC1R gene, Rongchang pigs were demonstrated to have the same dominant black allele (E(D1)) as other Chinese breeds, supporting the previous conclusion that Chinese and Western pigs have independent domestication origin. We also clarified that the Rongchang white phenotype was recessive to nonwhite color phenotypes. Our results provide a good starting point for the identification of the mutations underlying the white coat color in Rongchang pigs.
Alleles↗
Homozygosity for a severe novel medium-chain acyl-CoA dehydrogenase (MCAD) mutation IVS3-1G > C that leads to introduction of a premature termination codon by complete missplicing of the MCAD mRNA and is associated with phenotypic diversity ranging from sudden neonatal death to asymptomatic status.
Virtually all patients with medium-chain acyl-CoA dehydrogenase deficiency (MCADD) are homozygous or compound heterozygous for the 985A > G mutation, which limits the study of a possible genotype/phenotype correlation. A newborn Palestinian infant died suddenly on the second day of life. A previous sibling had also died in similar circumstances aged 3 weeks. Urine organic acid and bloodspot acylcarnitine analysis were consistent with MCADD. He was homozygous for a novel MCAD splice mutation, IVS3-1G > C. This mutation leads to deletion of 7 bp and introduction of a premature termination codon as a result of complete missplicing of MCAD mRNA. This misspliced MCAD mRNA encodes a non-functional protein and is furthermore reduced in amounts due to nonsense-mediated decay, resulting in total lack of functional MCAD enzyme. This is the first molecular identification of MCADD in an Arab patient and the first reported splice mutation in the MCAD gene that has been functionally characterized. The association of homozygosity for a null mutation with lethal neonatal presentation in the index patient and presumably the previous infant suggested a genotype/phenotype correlation. However, a 6-year-old completely asymptomatic sibling also had the characteristic MCADD biochemical phenotype and was homozygous for the same IVS3-1G > C mutation. As a first candidate to modify the disease presentation, by modulating the overlapping enzyme activity, we tested the entire family for the prevalent SCAD gene 625G > A susceptibility variant. Interestingly, all family members were 625G > A homozygous. Additional genetic and/or environmental factors must play a major role in determining the phenotypic diversity of MCADD.
Acyl-CoA Dehydrogenase↗
G to T transversion at position +5 of a splice donor site causes skipping of the preceding exon in the type III procollagen transcripts of a patient with Ehlers-Danlos syndrome type IV.
We identified a splicing mutation in a patient with Ehlers-Danlos syndrome type IV, a heritable connective tissue disorder associated with dysfunctions of type III collagen. The mutation was first localized in the patient's type III procollagen mRNA by amplifying the reverse transcribed product in several overlapping fragments using the polymerase chain reaction. Amplified products spanning exon 24-26 sequences displayed two distinct fragments, one of normal size and the other lacking the 99 base pairs of exon 25. Sequencing of amplified genomic products identified a G to T transversion at position +5 of the splice donor site of intron 25 in one of the patient's procollagen III genes. Expression of allelic minigene constructs correlated the T for G substitution with skipping of exon 25 sequences. Like previously characterized splicing mutations in other collagen genes, lowering the temperature at which the patient's fibroblasts were incubated nearly abolished exon skipping. As a part of this study, we also identified a highly polymorphic, intronic DNA sequence whose different allelic forms can be detected easily by the polymerase chain reaction technique.
Alleles↗