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PubMed1995

Molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical, and biological implications.

Mucopolysaccharidosis type I (MPS-I) is an autosomal recessive disease caused by mutations in the alpha-L-iduronidase (IDUA) gene. These mutations lead to a deficiency of the glycosidase alpha-L-iduronidase (IDUA), which is required for the degradation of heparan sulphate and dermatan sulphate and thus the storage of these glycosaminoglycans in the lysosome. There is a wide range of clinical phenotypes in MPS-I (eponyms: Hurler syndrome, severe; Hurler/Scheie syndrome, intermediate; Scheie syndrome, mild), which makes prediction of disease severity and genetic counselling difficult. However, since cloning of the IDUA gene, mutation analysis has provided some molecular explanations for the range of MPS-I phenotypes, in turn facilitating the selection and evaluation of patients undergoing experimental treatment protocols such as bone marrow transplantation. A total of 46 mutations now have been defined for MPS-I consisting of 8 nonsense mutations, 21 missense mutations, 3 splice site mutations, and 14 minor deletions and/or insertions. Furthermore, 30 polymorphisms or nonpathogenic sequence variants have been defined, including 7 amino acid substitutions. Among patients of European origin, there are two major MPS-I mutations and a number of less frequent mutations. It is possible to follow mutation analysis of 292 patients, which can be divided into eight main patient groups of different ethnic and/or geographic origin with significant variation in mutant allele frequencies. A complex picture of molecular heterogeneity is emerging, building a valuable database for genotype/phenotype correlation. Mutation analysis is also providing some of the first clues into the structure and function of IDUA.

Codon, Nonsense↗
PubMed2004

Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer.

The identification of tumor-suppressor genes in solid tumors by classical cancer genetics methods is difficult and slow. We combined nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for the genome-wide identification of genes with biallelic inactivation involving nonsense mutations and loss of the wild-type allele. This approach enabled us to identify previously unknown mutations in the receptor tyrosine kinase gene EPHB2. The DU 145 prostate cancer cell line, originating from a brain metastasis, carries a truncating mutation of EPHB2 and a deletion of the remaining allele. Additional frameshift, splice site, missense and nonsense mutations are present in clinical prostate cancer samples. Transfection of DU 145 cells, which lack functional EphB2, with wild-type EPHB2 suppresses clonogenic growth. Taken together with studies indicating that EphB2 may have an essential role in cell migration and maintenance of normal tissue architecture, our findings suggest that mutational inactivation of EPHB2 may be important in the progression and metastasis of prostate cancer.

Cell Line, Tumor↗
PubMed2004

Mutational analysis of the tyrosine phosphatome in colorectal cancers.

Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs (PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers. Fifteen mutations were nonsense, frameshift, or splice-site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP (PTPRT) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the mutated tyrosine phosphatases are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.

Catalytic Domain↗
PubMed2026

Prenatal diagnosis of glucose-6-phosphatase catalytic subunit 3 deficiency (Dursun syndrome) using whole-exome sequencing: A case report of severe fetal cardiomyopathy in a consanguineous family.

Glucose-6-phosphatase catalytic subunit 3 deficiency, also known as Dursun syndrome, is a rare autosomal recessive disorder characterized by severe congenital neutropenia and variable multisystem malformations, particularly affecting the cardiovascular system. Most reported cases have been identified postnatally, following infectious or hematologic complications. Prenatal identification remains exceptionally rare. We describe the case of a fetus from consanguineous parents with a history of multiple neonatal deaths. Serial prenatal imaging demonstrated progressive fetal growth restriction, cardiomegaly with biventricular hypertrophy, significant tricuspid regurgitation, right-sided cardiac dominance, right atrial enlargement, ventriculomegaly, and evolving craniofacial dysmorphism. Whole-exome sequencing revealed a homozygous nonsense variant in G6PC3 (NM_138387.3:c.481C > T; p.(Arg161Ter)), confirming that both parents were heterozygous carriers. Postnatally, the neonate developed severe neutropenia, complex right-sided cardiac outflow obstruction physiology, and refractory cardiorespiratory failure, leading to death on day 4 of life. This report expands the prenatal phenotypic spectrum of glucose-6-phosphatase catalytic subunit 3 deficiency and emphasizes the importance of considering this diagnosis in fetuses presenting with cardiomyopathy, dysmorphic features, fetal growth restriction, and parental consanguinity. Early molecular diagnosis enables accurate counseling, informed reproductive planning, and consideration of preconception or early prenatal genomic testing in high-risk families.

Humans↗
PubMed2000

Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome.

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

Abnormalities, Multiple↗
PubMed2004

Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer.

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.

Anodontia↗
PubMed2002

A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans.

Athabascan SCID (SCIDA) is an autosomal recessive disorder found among Athabascan-speaking Native Americans and is manifested by the absence of both T and B cells (T(-)B(-)NK(+) SCID). We previously mapped the SCIDA gene to a 6.5-cM interval on chromosome 10p. SCIDA fibroblasts were found to have defective coding joint and reduced, but precise signal joint formation during V(D)J recombination. After excluding potential candidate genes, we conducted a combined positional candidate and positional cloning approach leading to the identification of nine novel transcripts in the refined SCIDA region. One of the transcripts showed significant homology with the mouse and yeast SNM1/PSO(2) and was recently reported (Artemis) to be responsible for another T(-)B(-)NK(+) SCID condition (radiation sensitive SCID) in 13 patients of primarily European origin. In our evaluation of this gene, we have identified a unique nonsense mutation in 21 SCIDA patients that is closely correlated to the founder haplotypes that we had previously identified. This nonsense founder mutation results in the truncation of the deduced protein product. The wild-type construct of the primary transcript can effectively complement the defective coding joint and reduced signal joint formation in SCIDA fibroblasts. The above results indicate that this SNM1-like gene (Artemis) is the gene responsible for SCIDA. We also discovered three additional alternative exons and detected at least six alternatively spliced SCIDA variants (SCIDA-V1, 2, 3, 4, 5, and 6) coexisting with the primary transcript in trace amounts. Finally, we found that the SCIDA primary transcript (Artemis) encodes a nuclear protein.

Adult↗
PubMed2001

Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.

DNA mismatch repair is of considerable scientific and medical importance because of its essential role in maintaining genomic integrity, and its association with hereditary non-polyposis colon cancer (HNPCC). Germline mutations in five mismatch repair genes (MLH1, MSH2, PMS1, PMS2, and MSH6) have been associated with HNPCC susceptibility. Our laboratory recently identified MLH3, a novel DNA mismatch repair gene. We screened the MLH3 coding sequence in 60 probands with increased genetic risk factors for colorectal cancer susceptibility and no mutations in the other candidate genes. No definite MLH3 germline mutations were found. We subsequently screened 36 colon tumors, and discovered an appreciable frequency of somatic MLH3 coding mutations in MSI-H tumors (25%). In four of six tumors, evidence of biallelic inactivation was noted. Furthermore, MLH3 nonsense mutations were identified in two of 12 microsatellite stable (MSS) tumors with 14q24 loss of heterozygosity. While our analyses do not exclude the existence of germline MLH3 mutations in patients with increased genetic risk factors for colorectal cancer susceptibility, they suggest such mutations are uncommon in this patient population. The finding of an appreciable frequency of somatic MLH3 mutations is consistent with a possible role for this gene in the progression of colorectal cancer tumorigenesis. Hum Mutat 17:389-396, 2001. Published 2001 Wiley-Liss, Inc.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

Low-density lipoprotein receptor (LDLR) gene mutations cause familial hypercholesterol-emia (FH), one of the most common single gene disorders. The spectrum of LDLR mutations in Brazil is not known. The aim of this study was the characterization of LDLR mutations in 35 unrelated Brazilian patients with heterozygous FH. The promoter region, the 18 exons and the flanking intron sequences of the LDLR gene were screened by PCR-SSCP analysis and by DNA sequencing. In addition, we have screened the apolipoprotein B gene (APOB) for known mutations (R3500Q and R3531C) that cause Familial defective apo B-100 (FDB) by PCR-RFLP procedure. We found two nonsense (E92X and C371X) and six missense LDLR mutations (R236W, G322S, G352D, A370T, C675W and C677Y), that were previously described in FH patients from other populations. We also found five novel missense [G(-20)R, T476P, V503G, D580H and S652R] and two novel frame shift LDLR mutations (FsR757 and FsS828). Four patients were found to carry two different mutations in the LDLR gene: G352D and A370T (one patient), S652R and C675W (one patient) and T476P and V503G (two patients). APOB mutations were not found. These findings demonstrate that there is a broad spectrum of mutations in the LDLR gene in FH individuals from Brazil.

Adult↗
PubMed2000

Canine cystinuria: polymorphism in the canine SLC3A1 gene and identification of a nonsense mutation in cystinuric Newfoundland dogs.

Cystinuria is an inherited renal and intestinal disease characterized by defective amino acid reabsorption and cystine urolithiasis. Different forms of the disease, designated type I and non-type I in cystinuric humans, can be distinguished clinically and biochemically, and have been associated with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Type I cystinuria is the most common form and is inherited as an autosomal recessive trait in humans. Cystinuria has been recognized in more than 60 breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Here we report the cloning and sequencing of the canine SLC3A1 cDNA and gene, and the identification of a nonsense mutation in exon 2 of the gene in cystinuric Newfoundland dogs. A mutation-specific test was developed for the diagnosis and control of cystinuria in Newfoundland dogs. In cystinuric dogs of six other breeds, either heterozygosity at the SLC3A1 locus or lack of mutations in the coding region of the SLC3A1 gene were observed, indicating that cystinuria is genetically heterogeneous in dogs, as it is in humans. The canine homologue of human type I cystinuria provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases.

Amino Acid Sequence↗
PubMed2001

Severe factor VII deficiency with recurrent intracranial haemorrhages owing to double heterozygosity for a splice site mutation of an IVS4 and a novel nonsense mutation in exon 8 (Gln211-->Term).

Genetic analysis of a 10-month-old Japanese baby boy with recurrent intrathoracic bleeding, cerebral haemorrhages and gastrointestinal bleeding secondary to severe factor VII (FVII) deficiency revealed evidence of two distinct mutations of FVII: a splice site mutation of G-->A at nucleotide 6071 in the IVS4 splice site and a novel nonsense mutation (Gln211-->Term) in exon 8. His bleeding was difficult to control without prophylactic infusion of FVII. We detected a heterozygous splice site mutation of the IVS4 in his mother and a heterozygous nonsense mutation in exon 8 (Gln211-->Term) in his father. The parents' FVII levels are both 50% of normal controls. The FVII:C in plasma from the proband was < 1.5% of normal controls. FVII:antigen (Ag) was < 1% of normal controls, using a monoclonal antibody (mAb) hVII-B101/1 that specifically reacts with FVII epidermal growth factor 1 (EGF-1), and 5% of normal controls, using a rabbit polyclonal antibody against human FVII. After immunoadsorption with mAb hVII-B101/B1-Sepharose 4B, FVII levels of both the proband and his mother were 5% of normal controls; after immunoadsorption the FVII levels of normal subjects were < 1%. We hypothesize that secretion of a small amount of dysfunctional FVII lacking EGF-1 into the circulation accounts for this observation.

Codon, Nonsense↗
PubMed2002

A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes.

Vlad tepes (vlt(m651)) is one of only five "bloodless" zebrafish mutants isolated through large-scale chemical mutagenesis screening. It is characterized by a severe reduction in blood cell progenitors and few or no blood cells at the onset of circulation. We now report characterization of the mutant phenotype and the identification of the gene mutated in vlt(m651). Embryos homozygous for the vlt(m651) mutation had normal expression of hematopoietic stem cell markers through 24 h postfertilization, as well as normal expression of myeloid and lymphoid markers. Analysis of erythroid development revealed variable expression of erythroid markers. Through positional and candidate gene cloning approaches we identified a nonsense mutation in the gata1 gene, 1015C --> T (Arg-339 --> Stop), in vlt(m651). The nonsense mutation was located C-terminal to the two zinc fingers and resulted in a truncated protein that was unable to bind DNA or mediate GATA-specific transactivation. A BAC clone containing the zebrafish gata1 gene was able to rescue the bloodless phenotype in vlt(m651). These results show that the vlt(m651) mutation is a previously uncharacterized gata1 allele in the zebrafish. The vlt(m651) mutation sheds new light on Gata1 structure and function in vivo, demonstrates that Gata1 plays an essential role in zebrafish hematopoiesis with significant conservation of function between mammals and zebrafish, and offers a powerful tool for future studies of the hematopoietic pathway.

3T3 Cells↗
PubMed2006

Upf1, an RNA helicase required for nonsense-mediated mRNA decay, modulates the transcriptional response to oxidative stress in fission yeast.

In the fission yeast Schizosaccharomyces pombe, oxidative stress triggers the activation of the Spc1/Sty1 mitogen-activated protein kinase, which in turn phosphorylates the Atf1/Pcr1 heterodimeric transcription factor to effect global changes in the patterns of gene expression. This transcriptional response is also controlled by Csx1, an RNA-binding protein that directly associates with and stabilizes atf1(+) mRNA. Here we report the surprising observation that this response also requires Upf1, a component of the nonsense-mediated mRNA decay (NMD) system. Accordingly, upf1Delta and csx1Delta strains are similarly sensitive to oxidative stress, and the effects of the mutations are not additive, suggesting that Upf1 and Csx1 work in the same pathway to stabilize atf1(+) mRNA during oxidative stress. Consistent with these observations, whole-genome expression profiling studies have shown that Upf1 controls the expression of more than 100 genes that are transcriptionally induced in response to oxidative stress, the large majority of which are also controlled by Atf1 and Csx1. The unexpected connection between an NMD factor and the oxidative stress response in fission yeast may provide important new clues about the physiological function of NMD in other species.

Activating Transcription Factor 1↗
PubMed2002

Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.

In this study, we have carried out molecular analysis of the AIRE (autoimmune regulator) gene in 11 patients (from 8 families) affected by autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, originating from a restricted area of Southern Italy (the Salento peninsula in Puglia). Of the 16 mutant AIRE alleles from the 8 probands studied, 12 carried a missense mutation (W78R in 9, P539L in 2, and P252L in 1), 2 carried the Q358X nonsense mutation, and 2 carried the 1058delT frameshift mutation. All these mutations except the 1058delT are novel. Each of the detected mutations either predicts a premature termination of the protein or results in a nonconservative amino acid change, most likely adversely affecting the function of the protein. The W78R missense mutation is relatively common in these patients, having been detected (in homozygosity or compound heterozygosity) in 6 of the 8 probands tested, indicating the presence of a founder effect. The results of this study contribute to the delineation of the molecular pathology of the AIRE gene and enhance our ability to perform a molecular diagnosis in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy.

Adolescent↗
PubMed2003

Progressive exercise intolerance associated with a new muscle-restricted nonsense mutation (G142X) in the mitochondrial cytochrome b gene.

We report a novel nonsense mitochondrial cytochrome b mutation (G15170A) in a 40-year-old woman with progressive exercise intolerance and lactic acidosis. Muscle biopsy showed several cytochrome c oxidase-positive ragged-red fibers, and reduced activities of respiratory chain complexes I and III. This mutation, resulting in the loss of 228 amino acids of the protein, was very abundant in the patient's muscle, but undetectable in lymphocytes and fibroblasts. Clinical and laboratory data indicate that this defect is the primary cause of the disease, thus adding a new mutation in the cytochrome b gene among the growing number of patients with exercise intolerance and lactic acidosis.

Acidosis, Lactic↗
PubMed2006

An engineered nonsense URA3 allele provides a versatile system to detect the presence, absence and appearance of the [PSI+] prion in Saccharomyces cerevisiae.

Common methods to identify yeast cells containing the prion form of the Sup35 translation termination factor, [PSI+], involve a nonsense suppressor phenotype. Decreased function of Sup35p in [PSI+] cells leads to read-through of certain nonsense mutations in a few auxotrophic markers, e.g. ade1-14. This read-through results in growth on adenine-deficient media. While this powerful tool has dramatically facilitated the study of [PSI+], it is limited to a narrow range of laboratory strains and cannot easily be used to screen for cells that have lost the [PSI+] prion. Therefore we have engineered a nonsense mutation in the widely used URA3 gene, termed the ura3-14 allele. Introduction of the ura3-14 allele into an array of genetic backgrounds, carrying a loss-of-function URA3 mutation and [PSI+], allows for growth on media lacking uracil, indicative of decreased translational termination efficiency. This ura3-14 allele is able to distinguish various forms of the [PSI+] prion, called variants, and is able to detect the de novo appearance of [PSI+] in strains carrying the prion form of Rnq1p, [PIN+]. Furthermore, 5-fluoroorotic acid, which kills cells making functional Ura3p, provides a means to select for [psi-] derivatives in a population of [PSI+] cells marked with the ura3-14 allele, making this system much more versatile than previous methods.

Alleles↗
PubMed2001

Molecular genetics of glycogen-storage disease type 1a in Chinese patients of Taiwan.

The mutation spectrum of the glucose 6-phosphatase (G6Pase) gene in Chinese patients with type 1a glycogen-storage disease of Taiwan was studied by PCR/RFLP, temporal temperature gradient gel electrophoresis, and direct DNA sequencing methods. In addition to the two most prevalent mutations, 727G --> T (44.4%) and R83H (36.1%), that were detected by RFLP analysis, five other mutations, 341delG, 933insAA, Q104X, I341N, and H119L were identified. The frameshift mutations (341delG and 933insAA) and the nonsense mutation (Q104X) that produce truncated proteins are predicted to be disease-causing. The missense mutation, I341N, occurring in the last transmembrane domain of the ER-bound enzyme, retains a small amount of residual activity of approximately 10%. Except for R83H, the mutations have been described only in Asians. H119L, however, is of particular interest because of the essential role of the catalytic histidine of phosphohydrolase. This amino acid is believed to be involved in the formation of the phosphoryl-enzyme intermediate during catalysis. The patient who was compound heterozygous for 727G --> T and H119L mutations had essentially no G6Pase activity in her liver biopsy. This observation is consistent with the importance of H119L in catalysis.

Base Sequence↗
PubMed2002

Hailey-Hailey disease: molecular and clinical characterization of novel mutations in the ATP2C1 gene.

Hailey-Hailey disease is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. Mutations in ATP2C1, the gene encoding a novel, P-type Ca2+-transport ATPase, were recently found to cause Hailey-Hailey disease. In this study, we used conformation-sensitive gel electrophoresis to screen all 28 translated exons of ATP2C1 in 24 Hailey-Hailey disease families and three sporadic cases with the disorder. We identified 22 different mutations, 18 of which have not previously been reported, in 25 probands. The novel mutations comprise three nonsense, six insertion/deletion, three splice-site, and six missense mutations and are distributed throughout the ATP2C1 gene. Six mutations were found in multiple families investigated here or in our previous study. Haplotype analysis revealed that two of these are recurrent mutations that have not been inherited from a common ancestor. Comparison between genotype and phenotype in 23 families failed to yield any clear correlation between the nature of the mutation and clinical features of Hailey-Hailey disease. The extensive interfamilial and intrafamilial phenotypic variability observed suggests that modifying genes and/or environmental factors may greatly influence the clinical features of this disease.

Calcium-Transporting ATPases↗