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PubMed1991

Molecular basis for hereditary antithrombin III quantitative deficiencies: a stop codon in exon IIIa and a frameshift in exon VI.

Antithrombin III (AT III) is an inhibitor of serine protease (serpin) comprising 432 amino acids. Quantitative AT III deficiencies are associated with a high risk of thrombotic disease. Although this risk is smaller in patients with qualitative AT III deficiencies, the molecular defects characterizing the latter have been the subject of many studies. However, in quantitative AT III deficiencies, only three mutations have been described: Pro 407 to Leu and A1a404 to Thr (both located in the C-terminal part of the AT III molecule) and also a frameshift in exon IIIa. Using the asymmetric polymerase chain reaction (PCR) and genomic DNA analysis by direct sequencing, we detected two mutations in three unrelated families: (i) a C----T transition in exon IIIa in two families, leading to the replacement of the codon corresponding to Arg 129 by a stop codon, and (ii) in the third family, insertion of an adenine in the codon corresponding to Phe 408, a highly conserved serpin amino acid. This insertion altered the reading frame and led to the appearance of a premature stop signal. Patients of all three families were heterozygous for their abnormality. These results show that asymmetric PCR and genomic DNA analysis by direct sequencing permit fast identification of the molecular basis of quantitative AT III deficiencies. It is concluded that in many cases the absence of AT III gene product probably results from point mutation, as previously observed for another serpin, alpha-1-antitrypsin.

Adolescent↗
PubMed2006

Human alpha2-globin nonsense-mediated mRNA decay induced by a novel alpha-thalassaemia frameshift mutation at codon 22.

We describe a novel alpha-thalassaemia determinant in a 3-year-old girl presenting a mild microcytic and hypochromic anaemia, and normal haemoglobin A2 level. Molecular studies revealed heterozygosity for a novel microdeletion (-C) at codon 22 of the alpha2-globin gene. As the frameshift mutation generates a premature translation termination codon at position 48/49, we investigated the effect of the nonsense codon on the alpha2-globin gene expression. Although it does not affect RNA splicing, the premature nonsense codon induces accelerated mRNA degradation. To our knowledge, this is the first time the nonsense-mediated mRNA decay has been reported to occur in human alpha-globin mRNA.

Codon, Nonsense↗
PubMed2005

Two novel frameshift mutations of the EBP gene in two unrelated Thai girls with Conradi-Hünermann-Happle syndrome.

Conradi-Hünermann-Happle syndrome, also known as X-linked dominant chondrodysplasia punctata (CDPX2), is characterized by skeletal abnormalities, cutaneous anomalies and cataracts. CDPX2 is caused by mutations in the emopamil-binding protein (EBP). We report two unrelated Thai female patients with clinically typical CDPX2, in which we discovered two novel and de novo frameshift mutations: 506-507delAG and 540-541delCC. This study demonstrates that EBP is the gene responsible for CDPX2 across different populations and extends the total number of confirmed mutations to 55.

Base Sequence↗
PubMed1996

An Iranian-Armenian LDLR frameshift mutation causing familial hypercholesterolemia.

We used polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis to detect a mutation in the low density lipoprotein receptor (LDLR) gene in a family of Iranian-Armenian origin. The mutation, designated FH Yrmeih, deletes two nucleotides from exon 10 of the LDLR gene, which causes a translational frameshift, whereby a truncated LDLR protein of the first 471 residues of the LDLR with an additional 41 abnormal residues and a premature stop codon would be created. The deletion was detected in a father and son with clinical features of heterozygous FH. To our knowledge this is the first pathogenetic LDLR mutation identified in FH patients of Iranian-Armenian ancestry.

Adolescent↗
PubMed2004

A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote.

A 62-year-old white man with a hemochromatosis phenotype was found to be heterozygous for the C282Y mutation of the HFE gene. The H63D and S65C mutations of HFE were not present. As most C282Y heterozygotes do not develop a hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed frameshift mutation was identified in exon 2 (c.del277; G93fs) that resulted in a premature stop-codon. There were no coding region mutations of the ferroportin gene (FPN1). We performed human leukocyte antigen (HLA) typing of the patient and his brother who was heterozygous for the C282Y HFE mutation unassociated with a hemochromatosis phenotype. They shared only C282Y and the HLA haplotype A*03, B*14; hence, the c.del277 mutation was linked to the HLA haplotype A*02, B*44 and therefore not on the same chromosome as the C282Y mutation. Thus, the present patient's only intact HFE protein is C282Y, and this may explain his hemochromatosis phenotype.

Amino Acid Sequence↗
PubMed2005

Frameshift and nonsense mutations in the gene for ATPase7B are associated with severe impairment of copper metabolism and with an early clinical manifestation of Wilson's disease.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism. The clinical phenotype of the disease is varied. It is proposed that this variation may be a result of differential functional disruption of ATPase7B (ATP7B) resulting from mutations in the gene ATP7B. We aimed to assess the relationship between specific mutational defects in ATP7B and divergence in the phenotypic expression of WD. One hundred and forty-two patients with clinically, biochemically and genetically diagnosed WD were included in the study. The phenotypic expression of WD was compared between patients with different types of mutations in ATP7B, detected by direct sequencing of exons 1-21 of the gene. Twenty-six mutations were identified in ATP7B; eleven of them were mutations predicted to result in the absence of a full-length normal protein [frameshift/nonsense mutations; classified as 'severe' mutations (SMs)], 14 were missense mutations (MMs) and one was a splice site mutation. Patients with one or two SMs on their alleles had lower serum copper and ceruloplasmin and were younger when the first symptoms of the disease appeared, compared with individuals with two MMs. The effect of SMs on the WD phenotype was dose-dependent. It is concluded that mutations within ATP7B are very heterogeneous. Frameshift and nonsense mutations are associated with a severe phenotype of WD.

Adenosine Triphosphatases↗
PubMed2005

Genomic characterization of KIR2DL4 in families and unrelated individuals reveals extensive diversity in exon and intron sequences including a common frameshift variation occurring in several alleles.

The KIR2DL4 gene including a portion of exon 1 through exon 9 was sequenced from two families and eight cell lines from the International Histocompatibility Workshop (IHWS). Two known alleles and eight variants were detected. Overall, there were five synonymous and three non-synonymous changes when the variants were compared to the coding sequences of the most closely related known alleles plus a common frameshift change in five of the variant alleles. Alignment of the new variants with all known alleles showed that the regions encoding the extracellular region and the cytoplasmic tail were the most polymorphic. Two non-synonymous changes, P146H and L161V, occurred in an extracellular immunoglobulin-like domain. Five of the eight variants had a single adenine deletion in the exon encoding the transmembrane region, potentially resulting in a truncated protein lacking the cytoplasmic tail. The distribution of the deletion variant among many KIR2DL4 alleles may explain the high frequency of this variation in the population. Four of the eight consanguineous IHWS cell lines were found to be heterozygous for KIR2DL4 carrying two alleles that differed from one another by a few nucleotide substitutions. Analysis of intron sequences in the families revealed the nature and distribution of interspersed repeat elements which comprise 46% of the KIR2DL4 nucleotide sequence and consist of 12 elements including six SINEs (13.73% of the total length), one LINE (12.41%), and five LTR elements (19.51%). The results revealed the presence of extensive diversity in the KIR2DL4 gene. This is the first extensive report providing both exon and intron data in related individuals.

Alleles↗
PubMed1996

The defective secretion of a naturally occurring alpha-1-antichymotrypsin variant with a frameshift mutation.

A newly found variant alpha-1-antichymotrypsin (ACT), ACT Isehara-2, has a deletion of two bases (AA) at codon 391 near the carboxyl terminus. This frameshift mutation caused a change in the amino acid sequence and generated 10 extra amino acids (408 amino acids total) [Tsuda, M., Sei, Y., Matsumoto, M., Kamiguchi, H., Yamamoto, Y., Shinohara, Y., Igarashi, T. & Yamamura, M. (1992) Hum. Genet. 91. 467-468]. The serum ACT levels in three unrelated heterozygotes with this mutant ACT gene were 37% 49% and 54% that of the normal individuals. To examine the reduced serum levels, the normal ACT and the mutant ACT created by site-directed mutagenesis were transfected into COS-7 cells for comparison. The value for the retention rate (intracellular ACT/total ACT) was apparently higher in the cells expressing mutant ACT Isehara-2 than those bearing the normal gene. In the pulse-chase experiments, the secretion of the synthesized mutant ACT into the medium was not observed, whereas the normal ACT was mostly secreted as a 64-kDa form. The endoglycosidase H digestion and an electron microscopic analysis indicated that the retained mutant ACT was present in the endoplasmic reticulum. These results provide the biochemical basis for the decreased serum ACT level of individuals with ACT Isehara-2, and suggest the importance of the carboxyl-terminal region for its secretion.

Amino Acid Sequence↗
PubMed2005

Insertion of a C in the exon 28 of integrin alphaIIb gene leading to a frameshift mutation is responsible for Glanzmann thrombasthenia in a Japanese case.

BACKGROUND: Glanzmann thrombasthenia (GT) is a hereditary bleeding disorder caused by a qualitative or quantitative defect in the integrin alphaIIbbeta3. OBJECTIVE: Our objective is to identify the gene mutation that resulted in GT. PATIENTS AND METHODS: The patient was a 66-year-old male with a history of frequent bleeding. The expression levels of the integrin proteins in the platelets were determined by flow cytometry and Western blot analysis. The sequences of genomic DNA and mRNA encoding for alphaIIb and beta3 were analyzed by the dye-terminator cycle sequencing method. For transfection experiments, expression vectors encoding for wild-type alphaIIb, mutated alphaIIb, beta3, green fluorescent protein (GFP) fusion wild-type alphaIIb, GFP fusion mutated alphaIIb and DsRed fusion beta3 were constructed. These vectors were transfected to COS-7 cells, and the expression levels were determined. RESULTS: The alphaIIb protein was remarkably reduced in the patient's platelets, and gene analysis showed that the patient possessed compound heterozygous mutations in the alphaIIb gene. One was a C --> G substitution at the splice acceptor site (- 3) of exon 26 (CAG -->GAG) and the other was the insertion of an additional C at the region including six C bases between 2911 and 2916 in exon 28 (InsC). Transfection experiments using COS-7 cells showed that alphaIIb containing InsC had expressed and formed a complex with beta3, but had not been transported to the Golgi apparatus. CONCLUSIONS: In the present study the novel mutation InsC, leading to a frameshift that affects the transmembrane domain and the cytoplasmic tail, was found to be responsible for GT.

Aged↗
PubMed2006

Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII.

BACKGROUND: Hemophilia A (HA) is an X-chromosome-linked recessive disorder. AIM: We report the case of a female HA patient with a moderate decrease of factor (F) VIII activity and antigen (FVIII:C 3.4%, FVIII:Ag 4.2%) and severe bleeding symptoms. METHODS: The patient's father had mild FVIII deficiency (FVIII:C 6.9%, FVIII:Ag 7.4%), and her mother had normal FVIII activity. The von Willebrand disease antigen and von Willebrand factor ristocetin cofactor activity were normal in all family members. The genomic DNA was extracted from the peripheral blood lymphocytes of the patient and her family members. Long-distance polymerase chain reaction (PCR) was employed to screen for the intron 22 inversion of the FVIII coding gene (F8). The F8 coding sequence was amplified with PCR and sequenced with an automatic sequencer. RESULTS: Two heterozygous mutations were identified in the patient: one a substitution of nucleotide 5981T by C that leads to a missense mutation Leu1975Pro, and the other an insertion of an 'A' between nucleotides 3,637 and 3,638 (3637_3638insA) that shifts the reading frame and predicts a premature stop codon downward. The mutation Leu1975Pro was identified in the father's F8; however, 3637_3638insA was a de novo mutation that occurred in the patient's maternal-derived F8. Real-time PCR was applied to analyze the level of ectopically F8 gene transcripts in the peripheral lymphocytes of family members. The ectopic transcripts of F8 of the patient were less abundant than the normal control (patient:normal control ratio 0.67), whereas her parents showed no significant difference from the normal control. CONCLUSION: The FVIII deficiency of the HA patient resulted from a de novo occurrence of a frameshift 3637_3638insA in her maternal-derived F8 and a novel missense mutation Leu1975Pro inherited from her father.

Child↗
PubMedDate not supplied

Analysis of micronuclear, macronuclear and cDNA sequences encoding the regulatory subunit of cAMP-dependent protein kinase of Euplotes octocarinatus: evidence for a ribosomal frameshift.

We have isolated and characterized the micronuclear gene encoding the regulatory subunit of cAMP-dependent protein kinase of the ciliated protozoan Euplotes octocarinatus, as well as its macronuclear version and the corresponding cDNA. Analyses of the sequences revealed that the micronuclear gene contains one small 69-bp internal eliminated sequence (IES) that is removed during macronuclear development. The IES is located in the 5'-noncoding region of the micronuclear gene and is flanked by a pair of tetranucleotide 5'-TACA-3' direct repeats. The macronuclear DNA molecule carrying this gene is approximately 1400 bp long and is amplified to about 2000 copies per macronucleus. Sequence analysis suggests that the expression of this gene requires a +1 ribosomal frameshift. The deduced protein shares 31% identity with the cAMP-dependent protein kinase type I regulatory subunit of Homo sapiens, and 53% identity with the regulatory subunit R44 of one of the two cAMP-dependent protein kinases of Paramecium. In addition, it contains two highly conserved cAMP binding sites in the C-terminal domain. The putative autophosphorylation site ARTSV of the regulatory subunit of E. octocarinatus is similar to that of the regulatory subunit R44 of Paramecium but distinct from the consensus motif RRXSZ of other eukaryotic regulatory subunits of cAMP-dependent protein kinases.

Amino Acid Sequence↗
PubMed2003

Card15 and Crohn's disease: healthy homozygous carriers of the 3020insC frameshift mutation.

OBJECTIVES: Single nucleotide variations in the CARD15 gene have recently been shown to be associated with Crohn's disease (CD). Of special interest is a cytosine insertion at position 3020 of exon 11 (3020insC), which leads to a stop codon, truncation of the CARD15 protein, and an altered function of CARD15. The aim of the study was to evaluate this frameshift mutation in Dutch, multiple-affected families with inflammatory bowel disease (IBD). METHODS: Ninety-three Caucasian, multiple-affected families with IBD were recruited by interviewing patients attending our department. Sixty-one probands had CD, and 32 probands ulcerative colitis (UC). The diagnosis of probands and affected family members was verified according to standard criteria. In addition, 81 healthy, unrelated controls were included. Genomic DNA was isolated from venous blood of all participants to determine the CARD15 3020insC mutation by using an allele-specific polymerase chain reaction, followed by agarose gel electrophoresis and DNA sequencing. RESULTS: Association with CARD15 3020insC was statistically significant for CD, but not for UC. In one of the multiple-affected families, middle-aged and elderly homozygous carriers were identified without CD. CONCLUSIONS: Although CARD15 3020insC appears to be etiologically important in CD, homozygous carriage does not always lead to IBD.

Adult↗
PubMed1999

A recurrent frameshift mutation in exon 19 of the type VII collagen gene (COL7A1) in Mexican patients with recessive dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is an inherited blistering skin disorder caused by mutations in the type VII collagen gene (COL7A1). In this study, we determined the molecular basis of autosomal recessive DEB in a 19-year-old Hispanic Mexican woman by PCR amplification of genomic DNA, heteroduplex analysis, and automated sequencing of heteroduplex bandshifts. This approach revealed a homozygous frameshift mutation, 2470insG, in exon 19 of COL7A1 and resulted in attenuated basement membrane zone expression of type VII collagen, a reduced number of anchoring fibrils at the dermal-epidermal junction, and a sub-lamina densa level of blister formation. Clinically, the patient had widespread trauma-induced skin fragility and complete loss of the nails, but had less pseudosyndactyly of the fingers and toes and milder mucosal involvement compared to most patients with the generalized form of this genodermatosis. We also screened 7 other Hispanic-Mexican patients with recessive DEB, none of whom were known to be related to this individual, for the mutation 2470insG using heteroduplex analysis and direct sequencing and detected this mutation on 7/14 alleles. Haplotype analysis using intragenic COL7A1 and flanking polymorphisms and microsatellite markers revealed that all the mutant alleles had arisen on similar allelic backgrounds, consistent with propagation of a common Hispanic Mexican ancestral haplotype. In view of the high allelic frequency of the mutation 2470insG in the patients studied, we recommend initial screening for this mutation when attempting to identify the molecular pathology of recessive DEB in Hispanic Mexican patients.

Adult↗
PubMed2026

Establishment of a Common Marmoset Lineage Carrying a Frameshift Mutation in SETD1A, a Schizophrenia Risk Gene.

Appropriate histone modifications are essential for maintaining functional chromatin structure and gene expression, and dysfunction of their regulators has been linked to a variety of diseases. Among these modifications, trimethylation of lysine 4 on histone H3 (H3K4me3) is a well-characterized epigenetic mark enriched at transcription start sites of actively transcribed genes. H3K4me3 regulates gene transcription by recruiting transcription factors, facilitating chromatin accessibility, and preventing DNA methylation. In mammals, methylation of H3K4 is catalyzed by a family of histone methyltransferases including SET domain containing 1A (SETD1A), which is primarily responsible for genome-wide deposition of H3K4me2/3. Loss-of-function variants in SETD1A, highlighting its critical role in brain development and cognitive function, are strongly associated with schizophrenia (SCZ) and other neurodevelopmental disorders, but the underlying mechanisms remain largely unclear. To better understand the epigenetic and neurobiological consequences of SETD1A dysfunction, non-human primate models can serve as a useful tool because of their close evolutionary relationship to humans and highly developed cognitive abilities. In this study, we established a genetically engineered common marmoset (Callithrix jacchus) lineage carrying a frameshift mutation in SETD1A, which is, to the best of our knowledge, the first non-human primate lineage carrying a mutation in an epigenetic regulatory gene associated with SCZ, and confirmed germline transmission of the mutant allele. In a comparison between fibroblasts derived from one SETD1A mutant and one wild-type marmoset, the mutant showed a lower SETD1A protein level, modest differences in H3K4me3 deposition, and broader differences in gene expression profiles. Although these molecular observations require validation using additional biological replicates, the establishment of this SETD1A mutant marmoset lineage provides a valuable platform for bridging molecular mechanisms with primate neurobiology and for investigating the role of epigenetic regulation in the pathophysiology of neuropsychiatric and neurodevelopmental disorders.

Animals↗
PubMed1996

NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations.

Staphylococcus aureus NorA protein is a transmembrane multidrug efflux pump that confers low-level resistance to hydrophilic fluoroquinolones. The norA gene promoter is active in Escherichia coli HB101. We have examined the genetic basis of norA-mediated resistance in E. coli by introducing a wild-type norA gene into HB101 in plasmid pCL1921, pBR322, or pUC18 exhibiting copy numbers that spanned a 22-fold range. Increased ciprofloxacin resistance correlated with norA transcript levels seen by Northern (RNA) analysis. Thus, contrary to some reports, a wild-type norA gene confers fluoroquinolone resistance in E. coli in a copy-number-dependent fashion and does not require mutational activation. Interestingly, a multicopy pUC19norA derivative gave transformants exhibiting a range of resistance phenotypes. The norA gene of one transformant carried a single base deletion (ATACAAT to AACAAT; the deleted base is underlined) in the putative--10 Pribnow box resulting in a promoter down-regulatory mutation; a second plasmid had acquired a frameshift producing a null mutation at codon 112. These mutations override the dual resistance-growth-inhibitory phenotype of high-copy-number norA plasmids. The results have implications for using the standard E. coli HB101 system to assess NorA function and potentially for plasmid-borne transmission of norA-mediated drug resistance.

Anti-Infective Agents↗
PubMed2005

Cloning and characterization of the glucosidase II alpha subunit gene of Trichoderma reesei: a frameshift mutation results in the aberrant glycosylation profile of the hypercellulolytic strain Rut-C30.

We describe isolation and characterization of the gene encoding the glucosidase II alpha subunit (GIIalpha) of the industrially important fungus Trichoderma reesei. This subunit is the catalytic part of the glucosidase II heterodimeric enzyme involved in the structural modification within the endoplasmic reticulum (ER) of N-linked oligosaccharides present on glycoproteins. The gene encoding GIIalpha (gls2alpha) in the hypercellulolytic strain Rut-C30 contains a frameshift mutation resulting in a truncated gene product. Based on the peculiar monoglucosylated N-glycan pattern on proteins produced by the strain, we concluded that the truncated protein can still hydrolyze the first alpha-1,3-linked glucose residue but not the innermost alpha-1,3-linked glucose residue from the Glc2Man9GlcNAc2 N-glycan ER structure. Transformation of the Rut-C30 strain with a repaired T. reesei gls2alpha gene changed the glycosylation profile significantly, decreasing the amount of monoglucosylated structures and increasing the amount of high-mannose N-glycans. Full conversion to high-mannose carbohydrates was not obtained, and this was probably due to competition between the endogenous mutant subunit and the introduced wild-type GIIalpha protein. Since glucosidase II is also involved in the ER quality control of nascent polypeptide chains, its transcriptional regulation was studied in a strain producing recombinant tissue plasminogen activator (tPA) and in cultures treated with the stress agents dithiothreitol (DTT) and brefeldin A (BFA), which are known to block protein transport and to induce the unfolded protein response. While the mRNA levels were clearly upregulated upon tPA production or BFA treatment, no such enhancement was observed after DTT addition.

Amino Acid Sequence↗
PubMed1997

Identification of a frameshift mutation resulting in premature termination and loss of cell wall anchoring of the PAc antigen of Streptococcus mutans GS-5.

Most strains of Streptococcus mutans possess a 190-kDa protein antigen (PAc) on their cell surfaces, while strain GS-5 produces extracellularly a 155-kDa PAc protein. The pac gene of strain GS-5 consists of 3,477 bp and codes for a protein of 1,158 amino acids. One insertion of an adenine into the 3,469th, 3,470th, or 3,471st position from the start codon results in a frameshift mutation at codon 1157 with subsequent termination after 3 additional codons.

Amino Acid Sequence↗
PubMed1991

Frameshift mutations in the bacteriophage Mu repressor gene can confer a trans-dominant virulent phenotype to the phage.

Virulent mutations in the bacteriophage Mu repressor gene were isolated and characterized. Recombination and DNA sequence analysis have revealed that virulence is due to unusual frameshift mutations which change several C-terminal amino acids. The vir mutations are in the same repressor region as the sts amber mutations which, by eliminating several C-terminal amino acids, suppress thermosensitivity of repressor binding to the operators by its N-terminal domain (J. L. Vogel, N. P. Higgins, L. Desmet, V. Geuskens, and A. Toussaint, unpublished data). Vir repressors bind Mu operators very poorly. Thus the Mu repressor C terminus, either by itself or in conjunction with other phage or host proteins, tunes the DNA-binding properties at the repressor N terminus.

Amino Acid Sequence↗