Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Mutation, Missense”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2001

A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot--Marie--Tooth disease type 1.

A novel mutation (Arg381Cys) in the second zinc-finger domain of early growth response 2 (EGR2) was identified in a late-onset Charcot--Marie--Tooth disease type 1 (CMT1) patient. This patient had initial symptoms of numbness and weakness in the leg at age 59, and a median nerve motor conduction velocity of 27 m/s. A sural nerve biopsy showed a severe loss of myelinated fibers with numerous onion bulbs. This is the first report of the EGR2 mutation presenting a late onset of CMT1 phenotype. Its mutation was a different amino acid substitution at codon 381 (Arg381His) which demonstrated congenital hypomyelinating neuropathy or early-onset CMT1. This report suggests that the EGR2 mutation represents divergent phenotypes at codon 381, which may be a mutation hotspot.

Aged↗
PubMed2001

A dysfunctional factor X (factor X San Giovanni Rotondo) present at homozygous and double heterozygous level: identification of a novel microdeletion (delC556) and missense mutation (Lys(408)-->Asn) in the factor X gene. A study of an Italian family.

Low levels of factor X (F.X) were detected in a 4-year-old boy who experienced acute lymphoblastic leukemia and bleeding manifestations. Laboratory data suggested the presence of a dysfunctional F.X molecule. Two novel F.X gene mutations were identified in the proband that was double heterozygous for both: a microdeletion (delC556) in exon VI resulting in a frameshift leading to a termination codon at position 226. This deletion was found in six family members with reduced F.X antigen and activity levels. A second mutation characterised by a G(1344)-->C transversion in exon VIII was detected in the proband resulting in a Lys(408)-->Asn substitution. This latter mutation was present in several asymptomatic family members from the paternal and the maternal side. The proband's sister was homozygous for the Lys(408)-->Asn substitution and exhibited low F.X activity with a normal antigen level. The naturally occurring F.X Lys(408)-->Asn (F.X(K408N)) variant was isolated from plasma of either homozygous or double heterozygous individuals. NH(2)-terminal sequencing of the heavy chain of F.X(K408N) failed to show any sequence abnormality in patients who were also carriers of the delC556, suggesting that this latter lesion accounted for the lack of F.X synthesis. Purified F.X Lys(408)-->Asn had an identical behaviour to normal F.X as judged by SDS-PAGE and immunoblotting. Clotting assay using purified F.X(K408N) and F.X-deficient plasma resulted in a laboratory phenotype similar to that observed in a homozygous subject for F.X Lys(408)-->Asn substitution. This is the first characterisation of a naturally occurring F.X variant with a mutation at the COOH-terminal end of the molecule.

Amino Acid Sequence↗
PubMed2001

Combined occurrence of a heterozygous missense mutation in the protein C gene and allelic exclusion of one protein S allele leading to severe venous thrombosis.

Individuals with more than one defect in the natural anticoagulant system exhibit an increased risk for thrombosis. We report on a family with two cases of combined protein C (PROC) and protein S (PROS) deficiency, five cases of isolated PROC deficiency Type I, and two cases of isolated PROS deficiency Type I. PROC and PROS deficiency were documented by functional and immunologic tests. The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at nt 8490, leading to an exchange of alanine 259 by threonine. The mutation was present in all family members with PROC deficiency. The carriers of the isolated PROC mutation were asymptomatic at ages of 4, 7, 10, 11, and 80 years. The combination of the PROC mutation with a PROS deficiency in two family members triggered venous thromboembolism at age 31 and 6 years, respectively. The PROS deficiency was associated with complete exclusion of one PROS allele. Two family members with isolated PROS deficiency are still asymptomatic at age 21 and 9 years, respectively. Our findings in this family suggest that the heterozygous mutation at codon 259 of the PROC gene represents a mild thrombotic risk factor and only confers a high thrombotic risk in combination with a second defect, such as the complete exclusion of one PROS allele.

Adult↗
PubMed2003

A novel missense mutation in the myosin binding protein-C gene is responsible for hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients.

OBJECTIVES: We studied the clinical features of hypertrophic cardiomyopathy (HCM) caused by a novel mutation in the myosin binding protein-C (MyBP-C) gene in patients and family members of Japanese descent. BACKGROUND: Previous reports have demonstrated that the clinical features of HCM associated with mutations in the MyBP-C gene include late onset and a favorable clinical course. Recently, some mutations in genes encoding sarcomeric proteins have been reported to be a cause of dilated cardiomyopathy (DCM), as well as HCM. However, mutations of the MyBP-C gene have not been reported as a cause of DCM up to now. METHODS: We analyzed MyBP-C gene mutations in 250 unrelated probands with HCM and in 90 with DCM. We used electrocardiography (ECG) and echocardiography to determine clinical phenotypes. RESULTS: We identified 17 individuals in 8 families (7 HCM, 1 DCM) with an Arg820Gln mutation in the MyBP-C gene. Overall, 2 (40%) of 5 carriers age >70 years displayed "burnt-out" phase HCM, and one of them had been diagnosed as having DCM before genetic identification. The disease penetrance in subjects age >50 years was 70% by echocardiography and 100% by ECG, and that in those age <50 years was 40% and 50%, respectively. CONCLUSIONS: Elderly patients with Arg820Gln mutation may show "burnt-out" phase HCM, and patients with this mutation may be included among those diagnosed as having DCM. Screening of patients with DCM, as well as HCM, for this mutation is of significant importance because patients with this mutation may be diagnosed clinically as having DCM.

Adolescent↗
PubMed2003

Neonatal convulsions and epileptic encephalopathy in an Italian family with a missense mutation in the fifth transmembrane region of KCNQ2.

Mutations in the voltage gated K(+)-channel gene KCNQ2 are known to cause benign familial neonatal convulsions (BFNC), which are characterized by a benign course, spontaneous remission and normal psychomotor development. Most KCNQ2 mutations can be predicted to truncate the protein. Only a few amino acid exchanges have been found, and their localization was restricted to either the pore region or the fourth or sixth transmembrane region (TM). We have now identified the first KCNQ2 mutation located within TM5, affecting a highly conserved serine in amino acid position 247 of the predicted protein. The clinical history of the two affected family members is not compatible with typical BFNC. The poor outcome in the index patient raises the question if at least some KCNQ2 mutations might increase the risk to develop therapy-resistant epilepsy. Additional studies are needed to evaluate the possibility of a causal relationship between KCNQ2 mutations and severe early infantile epilepsy.

Adult↗
PubMed2002

Molecular and functional characterization of a new X-linked chronic granulomatous disease variant (X91+) case with a double missense mutation in the cytosolic gp91phox C-terminal tail.

We report here two atypical cases of X-linked CGD patients (first cousins) in which cytochrome b(558) is present at a normal level but is not functional (X91+). The mutations were localized by single-strand conformational polymorphism of reverse transcriptase-polymerase chain reaction amplified fragments and then identified by sequence analysis. They consisted in two base substitutions (C919 to A and C923 to G), changing His303 to Asn and Pro304 to Arg in the cytosolic gp91phox C-terminal tail. Mismatched polymerase chain reaction and genomic DNA sequencing showed that mothers had both wild-type and mutated alleles, confirming that this case was transmitted in an X-linked fashion. A normal amount of FAD was found in neutrophil membranes, both in the X91+ patients and their parents. Epstein-Barr virus-transformed B lymphocytes from the X91+ patients acidified normally upon stimulation with arachidonic acid, indicating that the mutated gp91phox still functioned as a proton channel. A cell-free translocation assay demonstrated that the association of the cytosolic factors p47phox and p67phox with the membrane fraction was strongly disrupted. We concluded that residues 303 and 304 are crucial for the stable assembly of the NADPH oxidase complex and for electron transfer, but not for its proton channel activity.

Cell Membrane↗
PubMed1998

Contribution of two missense mutations (G71R and Y486D) of the bilirubin UDP glycosyltransferase (UGT1A1) gene to phenotypes of Gilbert's syndrome and Crigler-Najjar syndrome type II.

In our mutation analyses of bilirubin UDP glycosyltransferase (UGT1A1) gene, we encountered six patients with Crigler-Najjar syndrome type II who were double homozygotes for G71R and Y486D, a patient with Gilbert's syndrome who was a single homozygote for G71R and six patients with Gilbert's syndrome who were single heterozygote for G71R. To clarify the role of each mutation in the occurrence of the two syndromes, we made four mutant expression models. Relative UGT1A1 activity of a single homozygous model of G71R was 32.2+/-1.6% of normal, that of a single homozygous model of Y486D was 7.6+/-0.5%, that of a double homozygous model of G71R and Y486D was 6.2+/-1.6% and that of a heterozygous model of G71R was 60.2+/-3.5%. The decreased activities of the single homozygous model of G71R and the double homozygous model were at an appropriate level to be diagnosed as Gilbert's syndrome and CN-II, respectively. The activity of a single heterozygous model of G71R was somewhat high to develop to the phenotype of Gilbert's syndrome, suggesting the presence of additional factors for the etiology of Gilbert's syndrome.

Animals↗
PubMed2001

Superoxide dismutase gene mutations in Italian patients with familial and sporadic amyotrophic lateral sclerosis: identification of three novel missense mutations.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. The majority of the patients are sporadic cases (SALS), while 5-10% of the patients have a family history of ALS (familial ALS or FALS). Mutations in the gene coding for cytoplasmic Cu/Zn superoxide dismutase (SOD1) have been identified in about 20% of FALS cases. We found SOD1-gene mutations in five of 34 unrelated FALS, and in two of 44 SALS patients. Three FALS patients carried the previously described A4V (two cases) and L84F mutations (one case), while two FALS patients carried new missense mutations: a G12R substitution in exon 1, and a F45C substitution in exon 2, respectively. The newly identified mutations were both associated with a slowly progressive disease course. Two SALS patients carried the homozygous D90A and the heterozygous I113T mutation, respectively. In addition, in one SALS patient we identified an A95T amino acid substitution, that is apparently a non-pathogenic SOD1 variant. Our study increases the number of ALS-associated SOD1 gene mutations.

Adult↗
PubMed2002

De novo missense mutation in a constitutively expressed exon of the slow alpha-tropomyosin gene TPM3 associated with an atypical, sporadic case of nemaline myopathy.

We describe an atypical case of nemaline myopathy with an unusual distribution of muscle weakness who presented at 14 years of age with kyphoscoliosis. In this patient, we demonstrate heterozygosity for a de novo CGT-CAT (Arg167His) mutation in a constitutively expressed exon (exon 5) of slow alpha-tropomyosin (TPM3). This is the first mutation identified in a constitutively expressed exon of TPM3 in a nemaline myopathy patient, but is similar to recently described mutations in beta-tropomyosin (TPM2) associated with nemaline myopathy and mutations in fast alpha-tropomyosin (TPM1) which cause hypertrophic cardiomyopathy.

Adenosine Triphosphatases↗
PubMed2003

A novel homozygous missense mutation in the GNE gene of a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation.

An adult-onset hereditary inclusion body myopathy with sparing of the quadriceps muscle was originally described in Iranian Jews and assigned to a locus on chromosome 9p12-p13. Recently, mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene were reported to cause hereditary inclusion body myopathy and one type of distal myopathy in a world-wide distribution. Importantly, the lack of muscle inflammation was used to distinguish hereditary inclusion body myopathy from the sporadic form of inclusion body myopathy. We report a case of a quadriceps-sparing myopathy in a non-Jewish, Iranian patient with a high degree of muscle inflammation. A novel homozygous G-to-A mutation (128933G-->A) in exon 7 changing a valine to isoleucine (V367I) in the epimerase domain of the GNE gene was found. We conclude that muscle inflammation is not sufficient to exclude the diagnosis of hereditary inclusion body myopathy.

Adult↗
PubMed2002

Biochemical defects in eight SRY missense mutations causing XY gonadal dysgenesis.

Sex determining Region of the Y chromosome (SRY) is the Y-borne gene required for male sex determination. Many XY females with complete gonadal dysgenesis carry SRY mutations. We describe here the effects of eight clinically isolated point mutations on the DNA-binding and -bending functions of SRY. We found that the seven mutations in the HMG domain affected the protein's DNA-binding and -bending activities to varying degrees, although all cause complete gonadal dysgenesis. DNA binding was abolished by the R75N and L94P mutations, severely disrupted by the F67V mutation and reduced by the M64R (6-fold), R76P (4-fold), A113T (3-fold), and M78T (1.7-fold) mutations. Of these, variant M64R showed no DNA-bending activity, while M78T caused a mild reduction in DNA bending. The S18N mutation, a familial mutation that lies outside the HMG domain and caused partial gonadal dysgenesis in one patient, had minimal effect on DNA binding and bending. Analysis of the NMR solution structure of the SRY HMG domain bound to DNA suggests that mutations disrupt the protein's conformation (helicity, packing), or interactions at the DNA interface. The degree to which mutations causing complete gonadal dysgenesis affect the DNA-binding activity varies. We propose that there is a threshold level of SRY activity or expression required for testis determination, as we observe that familial mutations have the least effect on SRY activity.

Amino Acid Sequence↗
PubMed2003

A novel missense mutation shows that GPIbbeta has a dual role in controlling the processing and stability of the platelet GPIb-IX adhesion receptor.

Glycoprotein (GP) Ibalpha is a major adhesive receptor of platelets, surface expressed as part of the GPIb-IX-V complex. However, important questions about how the four gene products (Ibalpha, Ibbeta, IX, and V) composing this complex are processed remain. A deficiency of or nonfunctioning GPIb-IX-V is characteristic of the Bernard-Soulier syndrome (BSS), an inherited bleeding disease. We now report a BSS variant whose platelets have little or no GIbbeta or GPIX, but where residual GPIbalpha was selectively located in flow cytometry by monoclonal antibodies (WM23 and Bx-1) recognizing denatured epitopes. Whereas WM23 immunoprecipitated GPIbalpha (130 kDa), GPIX, and GPIbbeta from control platelets, a single surface protein of approximately 66 kDa was obtained for the patient. DNA sequencing revealed a homozygous Asn(64) --> Thr substitution in the GPIbbeta from the patient. This substitution modified a conserved residue in the COOH-terminal region flanking the single-copy leucine-rich domain of GPIbbeta. When GPIbbeta64Thr was coexpressed in a stable CHO cell line with wild-type GPIbalpha and GPIX, flow cytometry and confocal microscopy failed to show GPIb-IX complexes at the cell surface. Intracellular GPIbalpha and GPIbbeta were detected and largely confined to the endoplasmic reticulum, and little GPIX was seen. GPIbalpha was immunoprecipitated as a 66-70 kDa protein in (35)S metabolic studies and lacked O-glycosidic side chains. Also, it was not disulfide bound to the mutated GPIbbeta. Thus, a single amino acid substitution in the extracellular domain of GPIbbeta can affect both the maturation of GPIbalpha and GPIX stability. GPIbbeta has a pivotal role in regulating GPIb-IX-V biosynthesis.

Adolescent↗
PubMed1999

Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.

The clinical use of molecular analyses in recessive disorders relies on the exact characterization of both mutant alleles in the affected patient. This can be problematic when only part of the gene is examined or when relevant DNA alterations are not recognized by standard methods. We present a child in whom phenylketonuria was apparently caused by homozygosity for the mutation E390G in exon 11 of the phenylalanine hydroxylase (PAH) gene. However, the clinical severity of the disease was not quite as mild as expected, the mutation was not identified in the father despite confirmed paternity, and the paternal allele showed a highly unusual pattern of polymorphic markers in the PAH gene. Presence of a large deletion involving exons 9, 10 and 11 of the phenylalanine hydroxylase gene was confirmed by long-range PCR. Diagnostic DNA analyses should include a comprehensive examination of the whole relevant gene in the patient and confirmation of carrier status in both parents.

DNA Mutational Analysis↗