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At least 1,009 records · Page 56Linked to original sources
PubMed2006

Ophthalmologic findings in Cornelia de Lange syndrome: a genotype-phenotype correlation study.

OBJECTIVE: To evaluate individuals with Cornelia de Lange syndrome previously screened for mutations in the NIPBL gene for genotype-phenotype correlations with regard to severity of ophthalmologic findings. METHODS: Fifty-four patients with Cornelia de Lange syndrome (26 mutation positive and 28 mutation negative) with varying extent and severity of ophthalmologic findings participated in the study. We conducted a retrospective analysis of ophthalmologic data obtained through survey responses and medical records. The severity of nasolacrimal duct obstruction, myopia, ptosis, and strabismus was classified. The severity of eye findings was compared relative to the presence vs the absence of mutations in the coding region of NIPBL and relative to mutations predicted to result in a truncated protein (nonsense and frameshift mutations) vs missense mutations. Fisher exact test was used to determine the significance of these correlations. RESULTS: A trend toward increased ptosis severity was found among individuals with truncating (nonsense and frameshift) mutations compared with individuals with missense mutations (P = .07). CONCLUSION: NIPBL may be directly involved in ptosis pathogenesis. CLINICAL RELEVANCE: Elucidating the pathogenetic mechanisms of ophthalmologic morbidities in patients with de Lange syndrome may lead to more effective treatment.

Adolescent↗
PubMed2005

Novel mutation in ABCC6 gene in a Japanese pedigree with pseudoxanthoma elasticum and retinitis pigmentosa.

PURPOSE: To report a novel mutation of the ABCC6 gene in a Japanese family that had a case of pseudoxanthoma elasticum (PXE) another with PXE and retinitis pigmentosa. METHODS: Ophthalmologic examinations were performed, and the ABCC6 gene was analysed by direct genomic sequencing. RESULTS: Fundus examinations of the 48-year-old proband disclosed angioid streaks and a peud'orange appearance of the retina of the both eyes, whereas both of his 25- and 20-year-old daughters had pigmentary degeneration and angioid streaks. In the sibilings, the mixed cone-rod ERG was almost nondetectable, whereas that of the proband was well-preserved. Molecular genetic analysis revealed that the proband has a homozygous nonsense mutation at the 595 bp in the ABCC6, and the siblings were heterozygous for the same mutation. This mutation was not detected in Japanese subjects in the JSNP database (http://snp.ims.u-tokyo.ac.jp/). CONCLUSIONS: Our results demonstrated an association between a novel mutation in the ABCC6 gene and PXE in a Japanese family.

Adult↗
PubMed2004

DNA-based prenatal diagnosis in a Chinese family with xeroderma pigmentosum group A.

BACKGROUND: Xeroderma pigmentosum (XP) is a group of autosomal recessive diseases characterized by hypersensitivity to ultraviolet rays. Among its eight complementation groups, XP group A (XPA) is the most severe type. The XPAC gene has been identified as the defective gene in XPA patients. OBJECTIVES: To examine genomic DNA from a Chinese family with XPA, to determine the XPAC mutation and, after genetic counselling, to undertake DNA-based prenatal diagnosis in a subsequent pregnancy. METHODS: Fetal DNA was extracted from amniotic fluid and used to amplify exon 5 of XPAC containing the potential mutation. Direct sequencing and restriction endonuclease digestion were used for prenatal diagnosis. RESULTS: We identified a homozygous nonsense XPAC mutation of 631C-->T, which results in an R211X mutation in XPA protein, in the proband. Both her parents are heterozygous. Prenatal diagnosis demonstrated a heterozygous sequence predicting an unaffected child, and a healthy girl was born. CONCLUSIONS: These data provide the first example of a DNA-based prenatal test for genodermatosis in China.

Child, Preschool↗
PubMed2005

A novel compound heterozygous mutation in Werner syndrome results in WRN transcript decay.

BACKGROUND: Werner syndrome (WS) is a rare autosomal recessive progeroid disorder caused by mutations of the WRN gene encoding a protein of the RecQ-type family of DNA helicases. OBJECTIVES: To develop a rapid and simple reverse transcription-polymerase chain reaction (RT-PCR) strategy for mutation analysis of the WRN gene, to identify pathogenic mutations in a German patient with WS and to determine the effects of the pathogenic mutations on WRN mRNA stability. METHODS: Allele-specific RT-PCR, semiquantitative RT-PCR, DNA sequencing. RESULTS: We describe a novel and rapid RT-PCR-based method for mutation analysis in WS and report a German patient with WS carrying a previously reported (1396delA) as well as a novel nonsense mutation (2334delAC) of the WRN gene. By semiquantitative RT-PCR analysis we demonstrate that this compound heterozygous genotype leads to WRN transcript decay. CONCLUSIONS: In previous studies WS was primarily attributed to a loss of function of stable truncated WRN gene products. Our findings indicate that mutations can also lead to markedly decreased WRN transcript stability.

Base Sequence↗
PubMed2005

A novel TITF-1 mutation causes benign hereditary chorea with response to levodopa.

Presented is a pedigree with infancy-onset benign hereditary chorea (BHC) caused by a novel nonsense mutation in exon 3 (523G-->T, E175X) of the TITF-1 (Nkx2.1) gene. Four confirmed mutation carriers showed the typical movement disorder of BHC and congenital hypothyroidism. Surprisingly, treatment with levodopa improved gait dramatically and reduced chorea in two patients. Dopaminergic drugs should be considered a useful therapeutic option in BHC.

Child↗
PubMed2002

Myophosphorylase deficiency (glycogenosis type V; McArdle disease).

McArdle disease, one of the most common metabolic causes of exercise intolerance and recurrent myoglobinuria, is due to biochemical defects of the muscle isoform of glycogen phosphorylase. The gene for myophosphorylase (PGYM) is on chromosome 11, and 33 distinct mutations have been identified in patients from all over the world. In Caucasians, a nonsense mutation in exon 1 (R49X) is common enough to warrant screening of genomic DNA from blood before considering muscle biopsy. Other mutations are prevalent in different ethnic groups or are "private". Mutations are spread throughout the gene and there is no clear genotype:phenotype correlation. High-protein diet and aerobic exercise are beneficial, and gene therapy appears promising.

Adolescent↗
PubMed1999

Detection of mutations in COL4A5 in patients with Alport syndrome.

Alport syndrome (AS) can be caused by mutations in COL4A5, one of the six type IV collagen genes. For the purposes of confirming diagnoses, carrier screening and correlating genotype to phenotype, we have screened all 51 exons of this gene by SSCP analysis in 153 families with suspected AS. Mutations were identified in 77 families (of which 20 have previously been reported) and are reported with all available clinical information. All types of mutation were found (missense, nonsense, splicing, small and large deletions and insertions), with the commonest type being those affecting glycine residues in the collagen triple helix. Our 50% detection rate is similar to that of other groups and may imply the presence of mutations outside of the COL4A5 coding region or the existence of a second X-linked AS gene.

Adolescent↗
PubMed2004

Phenotypic manifestations of MECP2 mutations in classical and atypical Rett syndrome.

Since the identification of mutations in MECP2 in girls and women with apparent Rett syndrome, numerous efforts have been made to develop phenotype-genotype correlations. These studies have produced conflicting results in part related to use of different clinical severity scales, different diagnostic criteria, and different stratification by age and mutation group as well as the possible effects of unbalanced X-chromosome inactivation. The present study applied a revised ordinal scoring system that allowed for correction for patient ages. We analyzed 85 patients with mutation in MECP2. Sixty-five (76%) had one of eight common mutations. Patients with missense mutations had lower total severity scores and better language performance than those with nonsense mutations. No difference was noted between severity scores for mutations in the methyl-binding domain (MBD) and the transcriptional repression domain (TRD). However, patients with missense mutations in TRD had the best overall scores and better preservation of head growth and language skills. Analysis of specific mutation groups demonstrated a striking difference for patients with the R306C mutation including better overall score, later regression, and better language with less motoric impairment. Indeed, these patients as a group accounted for the differences in overall scores between the missense and nonsense groups. Thus, the impact of specific mutations coupled with possible variation in X-chromosome inactivation must be considered carefully in the derivation of phenotype-genotype correlations. These results emphasize the limitations of such analyses in larger mutation groups, either by type or position.

Age of Onset↗
PubMed2002

Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor-cleaving protease by infusion of solvent/detergent plasma.

UNLABELLED: Plasma exchange or plasma infusion is considered to be the therapy of choice in patients with thrombotic thrombocytopenic purpura (TTP) who are deficient in von Willebrand factor-cleaving protease (VWF-CP). Recently, mutations in the ADAMTS 13 gene were identified as being responsible for VWF-CP deficiency in patients with familial TTP (VWF-CP deficiency in the absence of an inhibitor). Here we report on a girl who presented with recurrent thrombocytopenia and anaemia since birth, developing the full pentad of characteristic TTP at the age of 16 y. Congenital TTP was confirmed on the basis of severe VWF-CP deficiency in the absence of an acquired inhibitor. The patient was found to be compound heterozygous for two hitherto undescribed mutations in the ADAMTS 13 gene: a truncating frame shift mutation, 4143insA in exon 29, and the nonsense mutation 3100A >T in exon 24 (R1034X). After infusion of solvent/detergent plasma, the patient went into remission and remained asymptomatic under regular plasma therapy at 2-wk intervals for over two years. CONCLUSION: TTP in childhood may be mild and oligosymptomatic. Determination of VWF-CP activity is helpful in the differential diagnosis of thrombocytopenia.

ADAM Proteins↗
PubMed2001

Rhodopsin mutations in Chinese patients with retinitis pigmentosa.

AIM: To determine the pattern of rhodopsin mutations in Chinese retinitis pigmentosa (RP) patients. METHODS: The rhodopsin gene was examined in 101 RP patients and 190 controls from Hong Kong. RESULTS: Three coding changes were identified: Pro347Leu, Ala299Ser, and 5211delC. Each protein sequence alteration was found in one patient. Ala299Ser also existed in two controls. CONCLUSION: The C-terminal nonsense mutation may cause mis-sorting of rhodopsin protein. The finding of controls with Ala299Ser suggests this is only the third missense alteration reported that does not cause RP. The expected frequency of rhodopsin mutations in RP is <7% (2/101=2.0%, 95% confidence interval: 0.2%-7.0%).

Adult↗
PubMed2005

Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat.

Type 1 diabetes mellitus is an autoimmune disease involving both environmental and genetic factors. Genetic analyses in humans and rodents have shown that the major histocompatibility complex (MHC) is a major genetic factor and that several other genes may be involved in the development of the disease. We performed genetic analysis of type 1 diabetes in a newly established animal model, the Komeda diabetes-prone (KDP) rat, and found that most of the genetic predisposition to diabetes is accounted for by two major susceptibility genes, MHC and Iddm/kdp1. In addition, we identified a nonsense mutation in the Casitas B-lineage lymphoma b (Cblb) gene by positional cloning of Iddm/kdp1. In this paper, I review our positional cloning analysis of Iddm/kdp1 and propose a two-gene model of the development of type 1 diabetes in which two major susceptibility genes, Cblb and MHC, determine autoimmune reaction and tissue specificity to pancreatic beta-cells, respectively.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Heterozygosity for two novel null alleles of the KEL gene causes the Kell-null phenotype in a Japanese woman.

The Kell-null (Ko) phenotype is rare and it does not express the Kell antigens on erythrocyte membranes. Recently, several distinct missense and nonsense base substitutions in the coding region and the donor splice site of intron 3 were identified in the KEL gene in individuals with the Ko phenotype. We analysed both genomic DNA and cDNA sequences of the KEL gene in a Japanese woman with the Ko phenotype. She was found to be heterozygous for two novel null KEL alleles. One allele contained an A to G substitution in intron 5 that changes the 3'-splice site of intron 5 from AAG to AGG, resulting in a reading frameshift by a single guanine insertion in KEL mRNA, and the other allele contained a single G to A substitution in exon 12 (codon 459) creating a termination codon. Neither mutation was found in 114 randomly selected Japanese individuals. The results suggested that the Ko blood group phenotype might be owing to several distinct non-functional alleles without any prevalent allele.

Aged↗
PubMed2003

Two novel cases of cerebral haemorrhages at the neonatal period associated with inherited factor VII deficiency, one of them revealing a new nonsense mutation (Ser52Stop).

Factor VII (FVII) is a plasma glycoprotein that plays a key role in the initiation of blood coagulation cascade. Inherited FVII deficiency is a rare autosomal recessive disorder with a wide heterogeneous clinical pattern. The severe form may be associated with intracranial haemorrhages occurring closely to birth with a high mortality rate. In the present article, we report two novel cases of neonatal intracerebral bleeding associated with FVII activity levels below 1% of normal. FVII genotyping investigations revealed particular genotypes including the deleterious Cys135Arg mutation and a novel Ser52Stop nonsense mutation at the homozygous state. Both mutations, through different mechanisms, are expected to be inconsistent with the production of functional FVII. These putative mechanisms are discussed through a review of the literature on phenotypic and genotypic characteristics of cerebral haemorrhages in severe inherited FVII deficiency.

Base Sequence↗
PubMed2004

Nonsense-mediated messenger RNA decay is initiated by endonucleolytic cleavage in Drosophila.

In eukaryotic cells, messenger RNAs harbouring premature termination codons (PTCs) are rapidly degraded by a conserved post-transcriptional mechanism referred to as nonsense-mediated mRNA decay (NMD), which prevents the synthesis of truncated proteins that could be deleterious for the cell. Studies in yeast and mammals indicate that degradation by means of this pathway can occur from both the 5' end of the message (involving decapping and 5'-to-3' exonucleolytic digestion by XRN1) or the 3' end (through accelerated deadenylation and exosome-mediated 3'-to-5' decay). Here we show that, contrary to expectation, degradation of PTC-containing messages in Drosophila is initiated by endonucleolytic cleavage(s) in the vicinity of the nonsense codon. The resulting 5' fragment is rapidly degraded by exonucleolytic digestion by the exosome, whereas the 3' fragment is degraded by XRN1. This decay route is shown for several PTC-containing reporters, as well as an endogenous mRNA that is naturally regulated by NMD. We conclude that, despite conservation in the NMD machinery, PTC-containing transcripts are degraded in Drosophila by a mechanism that differs considerably from those described in yeast and mammals.

Animals↗
PubMed1999

Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.

Systemic primary carnitine deficiency (CDSP, MIM 212140) is a disorder of fatty acid oxidation manifesting in acute metabolic decompensation or in progressive cardiomyopathy and muscle weakness. Mutations in the plasmalemmal organic cation/carnitine transporter OCTN2 were recently identified in CDSP patients of diverse ethnic backgrounds. We have performed OCTN2 mutation analysis in two unrelated German patients with primary carnitine deficiency and identified three molecular abnormalities. On one of the four chromosomes analyzed, we detected an Arg169Gln missense mutation that affects an arginine residue absolutely conserved in the entire transporter superfamily to which OCTN2 belongs. On the three other chromosomes, we found an Arg282ter nonsense mutation in exon 5. This mutation is embedded into different haplotypes of closely spaced intragenic dimorphisms in our two patients and was recently described in a patient of Asiatic Indian background, so it appears to be a recurrent or ancient founder mutation that may account for more CDSP cases. Finally, we found that the Arg282ter nonsense mutation is associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations are present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the Arg282ter allele is due to an unconventional, long-distance mechanism.

Adolescent↗
PubMed2003

Co-occurrence of three different mutations in the bilirubin UDP-glucuronosyltransferase gene in a Chinese family with Crigler-Najjar syndrome type I and Gilbert's syndrome.

Crigler-Najjar syndrome type I is a severe form of hereditary unconjugated hyperbilirubinemia and is caused by homozygous or compound heterozygous mutations of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1). We analyzed the bilirubin UDP-glucuronosyltransferase gene in a female Chinese patient with Crigler-Najjar syndrome type I. Relatives of the patient were also analyzed. The patient was homozygous for a nonsense mutation of R341X. The patient's father, sister and brother, all diagnosed with Gilbert's syndrome, were compound heterozygotes of R341X, P229Q, and an insertion mutation of the TATA box [A(TA)7TAA]. Heterozygotes of nonsense mutations (Q331X and C280X) in our previous study had either Crigler-Najjar syndrome type II or Gilbert's syndrome, but heterozygotes of R341X (mother and grandmothers) were normal. An in vitro expression study of homozygous and heterozygous models of R341X showed 0 and 58%, respectively, of normal enzyme activity. Therefore, the present results indicate that carriers of the nonsense mutation could be normal for plasma bilirubin concentration, Gilbert's syndrome and Crigler-Najjar syndrome type II. The results also suggest the importance of the accumulation of prevalent or polymorphic mutation in the etiology of Gilbert's syndrome and Crigler-Najjar syndrome type II.

Adult↗
PubMed2006

Novel and de-novo truncating PAX6 mutations and ocular phenotypes in Thai aniridia patients.

PURPOSE: To describe the ophthalmic findings and mutation analyses of the PAX6 gene in Thai aniridia patients. METHODS: Ten patients from six unrelated families underwent a comprehensive ophthalmic examination. Mutations in the PAX6 gene were screened by single-strand conformational polymorphism (SSCP) and direct DNA sequencing of the SSCP variants. RESULTS: Seven patients developed cataracts and six developed glaucoma. Mutation analysis demonstrated four different truncating mutations, two of which were de novo. These included one novel insertion/deletion mutation (c.474del12insGA in exon 5) and three nonsense mutations. R203X and R240X are common recurrent mutations, while Q277X in exon 10 is novel. All mutations resulted in loss of function of the PAX6 protein. CONCLUSION: Our data confirm inter- and intrafamilial variable phenotypic manifestations of which the underlying mechanisms may be haploinsufficiency or dominant-negative mutation.

Adolescent↗
PubMed2005

Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome.

BACKGROUND: Congenital nephrotic syndrome (CNS) causes significant renal failure, and is classified into two types: (1) Finnish type; and (2) other, including diffuse mesangial sclerosis. Mutations of NPHS1 and NPHS2, which encode the slit diaphragm components nephrin and podocin, cause CNS and autosomal-recessive familial steroid-resistant nephrotic syndrome, respectively. Most patients with Finnish-type CNS in Europe and the United States have NPHS1 mutations. However, NPHS2 mutations have been detected in some cases. Mutations in ACTN4, encoding alpha-actinin-4, cause an autosomal-dominant focal segmental glomerulosclerosis. alpha-actinin-4 stabilizes the podocyte cytoskeleton structure, connecting with actin filaments. WT1 mutations, causing Wilm's tumor, have been demonstrated in some CNS patients with diffuse mesangial sclerosis. Systematic investigation of genes for CNS in Japan has never been performed. METHODS: To clarify the role of mutations in these four genes, we used polymerase chain reaction (PCR) and direct sequencing to investigate all exons and exon-intron boundaries for these genes in 13 unrelated CNS patients from regional pediatric kidney disease centers in Japan. RESULTS: A novel homozygous nonsense mutation of NPHS1, E246X in exon 7, and a novel homozygous deletion mutation of NPHS1, 2156_2163del in exon 16 were detected in one patient each. A novel homozygous nonsense mutation of NPHS2, R196X in exon 5, was found in one patient, and the same heterozygous nonsense mutation was detected in another. No ACTN4 or WT1 mutations were detected. CONCLUSION: These studies demonstrate that mutation of NPHS1 is not a major cause of CNS in Japanese patients, and that mutation of NPHS2 can be responsible for CNS in this population.

Actinin↗