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PubMed2005

Hearing loss associated with enlarged vestibular aqueduct and Mondini dysplasia is caused by splice-site mutation in the PDS gene.

Recessive mutations of PDS gene are the common causes of Pendred syndrome and non-syndromic hearing loss associated with temporal bone abnormalities ranging from isolated enlargement of the vestibular aqueduct (EVA) to Mondini dysplasia. In this study we evaluate the relationship between EVA and Mondini dysplasia in 10 prelingual deaf patients and PDS gene mutation. One of three mutations, IVS7-2A-->G, IVS16-6G-->A or IVS15+5G-->A, was identified in the PDS gene in each patient. In family studies of four probands with the IVS7-2A-->G mutation, we found that this mutation was inherited from the same mutant alleles of parental origin. The effect of IVS7-2A-->G mutation on PDS gene expression was determined by reverse transcription and polymerase chain reaction (RT-PCR). Sequencing of the RT-PCR products revealed that the PDS transcripts from the allele with IVS7-2A-->G mutation lose the entire exon 8, resulting in a joining of exons 7 and 9. Deletion of the exon 8 results in frameshift and premature termination of translation. Haplotype analysis showed a significant haplotype shared among the family members carrying IVS7-2A-->G mutation, suggesting that they may be derived from a common ancestor. Our results provide evidence that hearing loss with EVA and Mondini dysplasia may be caused by splice-site mutation in the PDS gene.

Adolescent↗

PubMed2002

Homozygous factor V splice site mutation associated with severe factor V deficiency.

We investigated a family whose proband has a severe bleeding disorder and factor V antigenic and functional levels of 8% and less than 1% of control values, respectively. Molecular analysis of the factor V gene revealed a novel homozygous mutation in the last nucleotide of exon 10. 1701G>T causes activation of a cryptic exonic splice site in exon 10, which encodes part of the factor V heavy chain (A2 domain). This leads to the deletion of 35 nucleotides and results in a frameshift with a premature stop codon at amino acid position 498. The G1701 and corresponding Gln509 are conserved in murine, bovine, and porcine factor V and in human factor VIII. Few factor V deficiency mutations have been identified as yet. Several are present in the heterozygous form in combination with factor V Leiden (Arg506Gln). This is the first reported homozygous splice site mutation in a patient with factor V deficiency.

Blood Transfusion↗

PubMed1994

Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.

We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2-36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.

Adenosine Triphosphatases↗

PubMedDate not supplied

A founder COL17A1 splice site mutation leading to generalized atrophic benign epidermolysis bullosa in an extended inbred Palestinian family from Israel.

PURPOSE: Generalized atrophic benign epidermolysis bullosa is a nonlethal form of junctional EB with an autosomal recessive inheritance. There is generalized cutaneous blister formation at sites of trauma, atrophic alopecia affecting scalp, eyelash and eyebrow, dystrophic nail changes, and tooth abnormalities. In this study, we have studied a five-generation Palestinian family affected with generalized atrophic benign epidermolysis bullosa. METHODS: We have performed linkage analysis to genes that are mutated in generalized atrophic benign epidermolysis bullosa, followed by direct sequencing of patient genomic DNA. RESULTS: We have shown that the disease is caused by a newly detected homozygous donor splice site mutation, IVS51+1G>A, in the type XVII collagen gene, COL17A1. CONCLUSION: The effect of a founder mutation introduced 3 to 4 generations before a disease appearance is demonstrated in this inbred family.

Autoantigens↗

PubMed1997

Autosomal recessive liver phosphorylase kinase deficiency caused by a novel splice-site mutation in the gene encoding the liver gamma subunit (PHKG2).

To facilitate mutation analysis of patients with an autosomal recessive form of liver phosphorylase kinase deficiency, the genomic structure of the gene encoding the testis/liver gamma subunit (PHKG2) was established. The gene consist of 10 exons. The translation start site is located in exon 2. Analysis of DNA from two female siblings, affected with liver phosphorylase kinase deficiency, by exon specific amplification followed by direct sequencing, revealed a single donor splice site mutation in the PHKG2 gene, IVS4 + 1(g --> a). The mutation leads to the skipping of exon 4, which results in a frameshift, starting at nucleotide 272, a premature stop codon after 32 additional amino acids, and subsequent loss of the catalytic site. It is concluded that deficiency of phosphorylase kinase in liver of the patients is caused by the IVS4 + 1(g --> a) mutation. In the patients described here, this genotype is associated with development of liver fibrosis.

Amino Acid Sequence↗

PubMed2002

Gonadal mosaicism of Frasier syndrome in 3 Chinese siblings with donor splice site mutation of Wilms' tumour gene.

Frasier syndrome is a rare human developmental disorder classically affecting 46,XY females and leading to male pseudohermaphroditism and chronic renal failure. We describe a family with both 46,XX and 46,XY females affected by the syndrome due to WT1 splice site mutations. The diagnosis of Frasier syndrome in 1 of the children led to the discovery of the syndrome in 2 other siblings, of whom 1 is asymptomatic. Since the mutation was not found in either parents, gonadal mosaicism was suggested. The implication of family screening for WT1 gene mutation in asymptomatic members is also discussed.

Adolescent↗

PubMed2004

Four new cases of congenital secondary hypothyroidism due to a splice site mutation in the thyrotropin-beta gene: phenotypic variability and founder effect.

Isolated TSH deficiency is a rare cause of congenital hypothyroidism. We here report four children from two consanguineous Turkish families with isolated TSH deficiency. Affected children who were screened at newborn age had an unremarkable TSH result and a low serum TSH level at diagnosis. Age at diagnosis and clinical phenotype were variable. All affected children carried an identical homozygous splice site mutation (IVS2 + 5 G--> A) in the TSHbeta gene. This mutation leads to skipping of exon 2 and a loss of the translational start codon without ability to produce a TSH-like protein. However, using specific monoclonal antibodies, we detected a very low concentration of authentic, heterodimeric TSH in serum, indicating the production of a small amount of correctly spliced TSH mRNA. By genotyping all family members with polymorphic markers at the TSHbeta locus, we show that the mutation arose on a common ancestral haplotype in three unrelated Turkish families indicating a founder mutation in the Turkish population. These results suggest that this TSHbeta mutation is among the more common TSHbeta gene mutations and stress the need for a biochemical and molecular genetic workup in children with symptoms suggestive of congenital hypothyroidism, even when the neonatal TSH screening is normal.

Adenine↗

PubMed1992

Beta-hexosaminidase splice site mutation has a high frequency among non-Jewish Tay-Sachs disease carriers from the British Isles.

In the course of defining mutations causing Tay-Sachs disease (TSD) in non-Jewish patients and carriers from the British Isles, we identified a guanine to adenine change (also previously described) in the obligatory GT sequence of the donor splice site at the 5' end of intron 9 of the hexosaminidase alpha peptide gene. Of 24 unrelated mutant chromosomes from 20 non-Jewish subjects (15 TSD carriers, four TSD patients, and one TSD fetus), five had mutations common in the Ashkenazi Jewish community, and 10 had the intron 9 splice site mutation. This is an unexpected result considering the diverse origin of the population of the British Isles. This mutation was not found in 28 control UK subjects or 11 Jewish carriers of known TSD mutations. Before attempting detection of unknown mutations, non-Jewish TSD carriers from the British Isles should be screened for the intron 9 donor splice site mutation as well as those mutations which predominate in the Jewish community.

Base Sequence↗

PubMed2004

[The mutation scanning of KCNQ1 gene for 31 long QT syndrome families].

OBJECTIVE: To search for the mutations of potassium voltage-gated channel, KQT-like subfamily member 1(KCNQ1) gene in 31 Chinese long QT syndrome(LQTS) families. METHODS: Due to the genetic heterogeneity, the genotype of patients was first predicted based on the spectrum of ST-T-wave patterns on ECG. Ten of 31 probands were considered as LQT1. Then the mutation of KCNQ1 gene was screened by the polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) technique combined with DNA sequencing in all members of these 10 families. To avoid omitting some LQT1 patients without typical characteristics and also to do methodological comparison, the mutations of KCNQ1 gene on 16 exons were screened by PCR and direct DNA sequencing in the rest 21 non-LQT1 probands only. Co-segregation analysis was carried out after the finding of an abnormal sequence. In case that the abnormality existed in patients only, the test of such exon was performed in 50 irrelevant normal individuals. RESULTS: Two missense mutations and three single nucleotide polymorphisms (SNPs) were found in the LQT1 predicted families. The two mutations were S277L (1 family) and G306V (1 family) in exon 5 and were not reported previously. Three polymorphisms were 435C-->T (7 families), 1632C-->A (1 family), and IVS1+9 C-->G (3 families). Only a splice mutation IVS1+5G-->A (2 families) and a polymorphism IVS10+18C-->T (1 family) were found in the non-LQT1 predicted probands. All three mutations were localized within the functional domain of KCNQ1 and were co-segregated with the disease, and were not found in 50 normal individuals. CONCLUSION: Two novel missense mutations, 1 splice mutation and four SNPs on KCNQ1 gene were found in the 31 LQTS families. Combined with ECG-based genotype prediction, PCR-SSCP could find most mutations on KCNQ1 and be a simple and economic method for screening LQTS.

Adolescent↗

PubMed2005

A novel constitutional mutation affecting splicing of retinoblastoma tumor suppressor gene intron 23 causes partial loss of pRB activity.

Hereditary predisposition to retinoblastoma is caused by germ line mutations in the RB1 gene. Genetic counseling of affected individuals and accurate risk prediction for their families requires identification of the disease causing mutation. Furthermore, the nature of a mutation can determine genetic penetrance, disease presentation and prognosis. We describe, and functionally characterize here, a novel mutant allele of RB1 present in the germ line of a patient with sporadic bilateral retinoblastoma. The mutation generates an operational splice acceptor site resulting in a predicted protein product with loss of 81 amino acids from its carboxy terminus. We demonstrate that the aberrantly spliced transcript is present in substantial amounts in peripheral blood of the patient and present evidence that the predicted protein product displays partial loss of activity reflecting in degree and presentation that of the partially penetrant RB1 missense mutant R661W. This infers that disease with reduced expressivity and incomplete penetrance may arise in individuals that carry the mutation and predicts such presentation for similar mutations with found in sporadic cases in the past.

Adult↗

PubMed1992

Nonsense mutations inhibit splicing of MVM RNA in cis when they interrupt the reading frame of either exon of the final spliced product.

mRNAs R1 and R2 of the autonomous parvovirus minute virus of mice (MVM), which encode the viral nonstructural proteins NS1 and NS2, respectively, are processed in an ordered splicing pathway in which R2 is generated from mature spliced R1. Introduction of translation termination signals into these genes alters the processing of these RNAs; there is a significant (up to fourfold) increase in the accumulated steady-state levels of R1 relative to R2, when compared with wild-type levels, although the total accumulated levels of R1 plus R2 remain the same. The increase in accumulated R1 relative to R2 in mutant infected or transfected murine cells is independent of RNA stability and transport and decreases, in a polar manner, with the distance of the inserted termination signal from the shared initiation codon for NS1 and NS2 at nucleotide 260. The increased ratio of R1 to R2 is a consequence of the artificially introduced translation termination signals acting in cis rather than in the absence of a functional viral gene product. These mutations have an effect when they interrupt previously open reading frames in either exon of the spliced product R2. Nonsense mutations that are located in the second exon of R2 inhibit splicing of R1 to R2 only when they interrupt an open reading frame (ORF) that has the potential, after normal splicing, to be joined in-frame with the initiating AUG. These results suggest that nonsense mutations inhibit splicing of R1 to R2 by influencing the mechanism by which exons are defined in murine cells.

Animals↗

PubMed2004

A novel splice site mutation in the WAS gene causes Wiskott-Aldrich syndrome in two siblings of a Saudi family.

We report here on a Saudi family with two affected males with Wiskott-Aldrich syndrome (WAS), which includes mild to moderate bleeding and a low platelet count. A novel splice donor-site mutation (811 + 5 G <-- C) in intron 8 of the WAS gene (Genbank accession number NM_000377) was detected in a hemizygous status in both index cases, heterozygous in their mother and absent in the father. RNA from both index cases was transcribed and amplified with primers complementary to sequences in exons 7 and 10. A reverse transcription-polymerase chain reaction (RT-PCR) product of 688 bp (approximately 82%) was produced in addition to the normal RT-PCR product of 485 bp (approximately 18%). cDNA sequence analysis reveals an inclusion of full intron 8 sequence in the final transcript. The resultant protein is predicted to have 68 missense codons and a pre-mature stop codon at amino acid 260. This novel splice donor-site mutation was not detected in 80 normal controls (56 females and 24 males) from the same ethnic background as the index cases. Since no other mutation was detected in the WAS gene and the patients have classical symptoms of WAS, we concluded that it is highly likely that this novel mutation is responsible for the phenotype observed in these patients.

Base Sequence↗

PubMed2003

Morphological changes in late onset acid Maltase deficient patients with splicing gene mutation.

Clinical and morphological features have been studied in 11 late onset Acid Maltase Deficient (AMD) patients. All patients have been diagnosed on biochemical evidence of acid maltase deficiency on muscle biopsy. Molecular studies showed a heterozygous mutation (IVS1-13 T > G transversion resulting in aberrant splicing) in the GSDII gene, which is the most common mutation in late onset AMD patients. Morphological features in muscle biopsy showed a vacuolar myopathy and Golgi apparatus proliferation within fibres. The peripheral areas of autophagic vacuoles were positive for caveolin-3 and dystrophin, documenting an extensive membrane turnover. The ultrastructural study of muscle biopsy showed randomly distributed or isolated vesicles sometimes derived from the Golgi apparatus. In subsarcolemmal region, lipofucsin bodies and abnormal mitochondria with crystalline inclusions were observed. Primary and secondary lysosomes were typically filled with glycogen. These data suggest a predominant role of Golgi in vesicle proliferation and extensive intra-fibral membrane remodelling. The pathological changes observed are selective for muscle fibres (mostly in type 1) and for muscle groups (mainly proximal). An attractive hypothesis for the variability of clinical phenotype in adult and infantile onset AMD patients is that in the former, an aberrant transcript of smaller size may have originated from alternative splicing (exon 2 skipping). A residual enzyme activity is detectable in muscle, but the intracellular processing of the enzyme precursor from Golgi to the mature form in lysosomes might be blocked.

Acid Phosphatase↗

PubMed1994

A splice junction mutation in a new myopathic variant of phosphoglycerate kinase deficiency (PGK North Carolina).

We report on a 12-year-old boy with the myopathic form of phosphoglycerate kinase (PGK) deficiency, and unique kinetic and physical characteristics of the mutant enzyme (PGK North Carolina). A G-to-T substitution at the 5' end of intron 4 was identified in the PGK gene of this patient. The mutation destroys the consensus sequence GT at the 5' splice junction of the intron. Activation of a cryptic splice site within intron 4 causes the insertion into the transcript of a 30-bp fragment at the 5' end of intron 4. This insertion results in ten additional amino acids within the "nose" of the PGK molecule, but does not generate a frameshift or a premature stop codon.

Base Sequence↗

PubMed2000

A KCNQ2 splice site mutation causing benign neonatal convulsions in a Scottish family.

Benign familial neonatal convulsions (BFNC) are one of the rare idiopathic epilepsies with autosomal dominant mode of inheritance. Two voltage-gated potassium channels, KCNQ2 on chromosome 20q13.3 and KCNQ3 on 8q24, have been recently identified as the genes responsible for BFNC. Here we describe a large family with BFNC in which we found a previously undescribed mutation in the KCNQ2 gene. A 1187(+2)T/G nucleotide exchange affects the conserved donor splice site motif in intron 9. This mutation can be predicted to give rise to aberrant splicing of the primary transcript. There was a wide range of clinical manifestations in this family. An unusual clinical feature is the occurrence of partial seizures in later life with corresponding focal neurological deficits.

Chromosome Aberrations↗

PubMed2006

A novel splice site mutation in the Cockayne syndrome group A gene in two siblings with Cockayne syndrome.

Cockayne syndrome (CS) is mainly caused by mutations in the Cockayne syndrome group A or B (CSA or CSB) genes which are required for a sub-pathway of nucleotide excision repair entitled transcription coupled repair. Approximately 20% of the CS patients have mutations in CSA, which encodes a 44 kDa tryptophane (Trp, W) and aspartic acid (Asp, D) amino acids (WD) repeat protein. Up to now, nine different CSA mutations have been identified. We examined two Somali siblings 9 and 12 years old with clinical features typical of CS including skin photosensitivity, progressive ataxia, spasticity, hearing loss, central and peripheral demyelination and intracranial calcifications. Molecular analysis showed a novel splice acceptor site mutation, a G to A transition in the -1 position of intervening sequence 6 (g.IVS6-1G>A), in the CSA (excision repair cross-complementing 8 (ERCC8)) gene. IVS6-1G>A results in a new 28 amino acid C-terminus and premature termination of the CSA protein (G184DFs28X). A review of the CSA protein and the 10 known CSA mutations is also presented.

Amino Acid Sequence↗

PubMed1997

Two different 5' splice site mutations in the growth hormone gene causing autosomal dominant growth hormone deficiency.

Four distinct types of isolated growth hormone deficiency (IGHD) have been described to date. Of these IGHD type II has been defined as having a dominant mode of inheritance. We performed a molecular genetic analysis of two patients clinically characterized as IGHD type II. One of the patients and her father shared a heterozygous G-A transition in the first 5' donor splice site of intron III. The second father and daughter studied also showed a heterozygous G-A transition in the fifth base from the 5' donor splice site in the same intron. Both mutations altered the correct splicing of the growth hormone pre-mRNA when the corresponding genes were expressed in COS-7 cells. We propose that both inherited mutations are responsible for IGHD type II in these patients.

Adult↗

PubMed2001

Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy.

OBJECTIVES: We studied the clinical and genetic features of hypertrophic cardiomyopathy (HCM) caused by mutations in the myosin-binding protein C gene (MYBPC3) in 110 consecutive, unrelated patients and family members of European descent. BACKGROUND: Mutations in the MYBPC3 gene represent the cause of HCM in approximately 15% of familial cases. MYBPC3 mutations were reported to include mainly nonsense versus missense mutations and to be characterized by a delayed onset and benign clinical course of the disease in Japanese and French families. We investigated the features that characterize MYBPC3 variants in a large, unrelated cohort of consecutive patients. METHODS: The MYBPC3 gene was screened by single-strand conformational polymorphism analysis and sequencing. The clinical phenotypes were analyzed using rest and 24-h electrocardiography, electrophysiology, two-dimensional and Doppler echocardiography and angiography. RESULTS: We identified 13 mutations in the MYBPC3 gene: one nonsense, four missense and three splicing mutations and five small deletions and insertions. Of these, 11 were novel, and two were probably founder mutations. Patients with MYBPC3 mutations presented a broad range of phenotypes. In general, the 16 carriers of protein truncations had a tendency toward earlier disease manifestations (33 +/- 13 vs. 48 +/- 9 years; p = 0.06) and more frequently needed invasive procedures (septal ablation or cardioverter-defibrillator implantation) compared with the 9 carriers of missense mutations or in-frame deletions (12/16 vs. 1/9 patients; p < 0.01). CONCLUSIONS: Multiple mutations, which include missense, nonsense and splicing mutations, as well as small deletions and insertions, occur in the MYBPC3 gene. Protein truncation mutations seem to cause a more severe disease phenotype than missense mutations or in-frame deletions.

Adolescent↗