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PubMed2001

DNA based molecular analysis in the rapid diagnosis of Herlitz junctional epidermolysis bullosa.

The junctional form of epidermolysis bullosa (JEB) is an inherited blistering disease in which blisters occur at the level of the lamina lucida in the cutaneous basement membrane zone. Specific mutations have been detected in the genes encoding different components of the hemidesmosomal-anchoring filament complex. In the recessively inherited lethal (Herlitz) type of JEB (H-JEB), typically nonsense mutations or insertions or deletions are present on both alleles of any of the three genes encoding the polypeptide subunits of the anchoring filament protein, laminin 5. In this study, we searched for mutations in a proband who presented at birth with severe and extensive blistering. We detected a novel 1 bp deletion and a previously reported hotspot mutation (R635X) in the LAMB3 gene. This mutation combination established the diagnosis of H-JEB in this case, in which attempted diagnosis by skin biopsy had failed. The molecular analysis was performed shortly after birth while the patient was admitted to the intensive care unit, and the definitive molecular diagnosis allowed the parents and physicians to devise management plans.

Cell Adhesion Molecules↗
PubMed2005

Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.

Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.

Adenosine Triphosphate↗
PubMed2004

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), an autosomal dominant inherited disorder associated with an increased risk of premature atherosclerosis. The aim of this study was to characterize the LDLR mutations in a group of 476 apparently non-related Spanish FH patients. The promoter region and the 18 exons with their flanking intron sequences of the LDLR gene were screened by PCR-SSCP analysis and DNA sequencing. In addition, we tested for the presence of the mutation p.R3500Q in the gene coding for apolipoprotein B-100 (apo B-100). We found 77 mutations previously described, and 39 novel mutations affecting the LDLR gene: 8 missense, 5 nonsense, 15 frameshift, 5 splicing, 4 in frame, one nucleotide change in the non-coding sequence of exon 1, and one silent variant. We have identified al least one of these LDLR gene mutations in 329 subjects (69%). Four patients were homozygous, 4 patients were compound heterozygous, 48 patients were found to carry two different sequence variants in the same allele and 4 patients carried three different sequence variants in the same allele. Additionally, 4 subjects were carriers of the p.R3500Q mutation in the apo B gene. All of these findings indicate that there is a broad spectrum of mutations and sequence variants in the LDLR gene causing FH in Spain.

Codon, Nonsense↗
PubMed2006

Germline mutations of the hMLH1 and hMSH2 mismatch repair genes in Belgian hereditary nonpolyposis colon cancer (HNPCC) patients.

BACKGROUND: Hereditary nonpolyposis colon cancer (HNPCC-Lynch syndrome) is caused by mutations in genes involved in DNA mismatch repair (MMR), mostly in the hMLH1 and hMSH2 genes. The mutation spectrum in the Belgian population is still poorly documented. AIM: To report our experience on the mutation screening in Belgian familial colorectal cancer (CRC) patients, including the investigation of the pathogenicity of the missense and splice mutations. To increase the mutation detection rate by selecting the target population. METHODS: Two hundred and twenty five Belgian patients with familial clustering of CRC were genetically tested. Point mutations in the hMLH1 and hMSH2 genes were screened by denaturing gradient gel electrophoresis (DGGE) followed by direct sequencing. Genomic deletions and duplications were assessed by multiplex ligase dependent probe amplification (MLPA) and multiplex PCR. Missense mutations were examined for pathogenicity by means of cosegregation of the mutation with the disease, microsatellite instability (MSI) in tumors, immunohistochemical staining of tumors and determination of the population frequency of the particular mutation. RESULTS: Twenty five pathogenic mutations were identified from which 16 were novel: 7 frameshifts, one in frame deletion, 5 genomic deletions, 5 splice defects, 4 nonsense (stop) mutations and 3 missense mutations which were classified as pathogenic (out of 10 missense mutations). In retrospect, a mutation detection rate of 71% was obtained if MSI was used as a supplementary selection criterion in addition to familial clustering. CONCLUSION: Different types of pathogenic mutations in the hMLH1 and hMSH2 genes were identified in a Belgian CRC group with familial clustering. The mutation detection yield drastically increased by preliminar selection of those familial CRC patients with a microsatellite instable tumor. Considerable attention went to the assessment of the pathogenicity of the missense mutations. In practice, the cosegregation with the disease was the most relevant criterion.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Functional characterization of Drosophila Translin and Trax.

The vertebrate RNA and ssDNA-binding protein Translin has been suggested to function in a variety of cellular processes, including DNA damage response, RNA transport, and translational control. The Translin-associated factor X (Trax) interacts with Translin, and Trax protein stability depends on the presence of Translin. To determine the function of the Drosophila Translin and Trax, we generated a translin null mutant and isolated a trax nonsense mutation. translin and trax single and double mutants are viable, fertile, and phenotypically normal. Meiotic recombination rates and chromosome segregation are also not affected in translin and trax mutants. In addition, we found no evidence for an increased sensitivity for DNA double-strand damage in embryos and developing larvae. Together with the lack of evidence for their involvement in DNA double-strand break checkpoints, this argues against a critical role for Translin and Trax in sensing or repairing such DNA damage. However, Drosophila translin is essential for stabilizing the Translin interaction partner Trax, a function that is surprisingly conserved throughout evolution. Conversely, trax is not essential for Translin stability as trax mutants exhibit normal levels of Translin protein.

Amino Acid Sequence↗
PubMed2000

X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3.

We report on a Lebanese family in which two maternal cousins suffered and died very early in life from cardiac malformations. Both presented with a transposition of the great arteries associated with one or several other cardiac defects. Various minor midline defects were also observed, but there were no situs abnormalities other than a persistent left superior vena cava in one. A maternal uncle of these two babies was born cyanotic and died on the third post-natal day. Analysis of the ZIC3 gene, revealed the presence of a mutation in the second exon leading to a truncation of the protein. Surprisingly, another maternal uncle of the two affected cousins also had the mutation but was not clinically affected. To our knowledge, this is the first instance of incomplete penetrance in a male for a mutation in a chromosome X gene.

Alternative Splicing↗
PubMed2003

Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency.

Succinate semialdehyde dehydrogenase (SSADH; ALDH5A1) deficiency, a rare metabolic disorder that disrupts the normal degradation of GABA, gives rise to a highly heterogeneous neurological phenotype ranging from mild to very severe. The nature of the mutation has so far been reported in patients from six families world wide and eight different mutations were described. Here we report the mutational spectrum in 48 additional unrelated families of different geographic origin. We detected 27 novel mutations at the cDNA level, of which 26 could be attributed to changes at the genomic level. Furthermore, six mutations were detected that did not strongly affect SSADH activity when expressed in HEK 293 cells and are considered nonpathogenic allelic variants. Twenty of the mutations were only found in one family. The spectrum of disease-causing mutations from all patients sequenced thus far consists of 25 point mutations, four small insertions, and five small deletions. Seven of these mutations affect splice junctions, seven are nonsense mutations, and 12 are missense mutations. Although there were no mutational hotspots or prevalent mutations responsible for a significant number of cases, 14 out of 37 (38%) of the missense alleles were present in exon 4 or 5. With one exception, the missense mutations we consider to be causative of SSADH deficiency reduced the SSADH activity to less than 5% of the normal activity in our in vitro expression system. This indicates that residual expression is not likely to be an important factor contributing to the large phenotypic differences observed among different families and even among siblings, suggesting that other modifying factors are of great importance in disease pathology.

Aldehyde Oxidoreductases↗
PubMed2001

Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population.

The gene MCOLN1 is mutated in Mucolipidosis type IV (MLIV), a neurodegenerative, recessive, lysosomal storage disorder. The disease is found in relatively high frequency among Ashkenazi Jews due to two founder mutations that comprise 95% of the MLIV alleles in this population [Bargal et al., 2000]. In this report we complete the mutation analysis of Jewish and non-Jewish MLIV patients whose DNA were available to us. Four novel mutations were identified in the MCOLN1 gene of severely affected patients: two missense, T232P and F465L; a nonsense, R322X; and an 11-bp insertion in exon 12. The nonsense mutation (R322X) was identified in two unrelated patients with different haplotypes in the MCOLN1 chromosomal region, indicating a mutation hotspot in this CpG site. An in-frame deletion (F408del) was identified in a patient with unusual mild psychomotor retardation. The frequency of MLIV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the two founder mutations. This analysis indicated a heterozygotes frequency of about 1/100. A preferred nucleotide numbering system for MCOLN1 mutations is presented and the issue of a screening program for the detection of high-risk families in the Jewish Ashkenazi population is discussed.

Codon, Nonsense↗
PubMed2005

[Mutation detection of mismatch repair genes in hereditary nonpolyposis colorectal cancer by denaturing high-performance liquid chromatography].

OBJECTIVES: To establish DHPLC method in detecting mutations of mismatch repair genes, hMLH1 and hMSH2, and to identify germline mutations of hMLH1 and hMSH2 in HNPCC kindreds fulfilling Chinese HNPCC criteria. METHODS: Fourteen peripheral blood DNA samples from 14 unrelated HNPCC probands fulfilling Chinese HNPCC criteria were obtained respectively. PCR amplified 35 exons of two main mismatch repair genes, hMLH1 and hMSH2. DHPLC followed by DNA sequencing was used to detect and confirm mutations. RESULTS: a total of 41 colorectal cancers and 19 extracolonic tumors were developed in 14 HNPCC kindreds, and gastric cancer was the most common extracolonic tumor type. Twelve single nucleotide changes were identified by DHPLC in 14 probands. Among them, three were missense mutations, one was a nonsense mutation. Other single nucleotide changes included five single nucleotide polymorphisms, two intron single nucleotide changes, one synonymous mutation. hMLH1 EXON19 CODON749 TAC-->TAG (Tyr-->X), hMSH2 EXON12 CODON629 CAA-->CGA (Gln-->Arg) and hMSH2 EXON15 CODON839 CAT-->CGT (His-->Arg) were new discovered mutations. CONCLUSIONS: (1) DHPLC was considered to be highly effective, convenient technique with consistent results for the mutation detection of hMLH1 and hMSH2 genes. (2) Valid mutations of hMLH1 and hMSH2 genes were identified in about one-third HNPCC kindreds fulfilling Chinese HNPCC criteria and missense mutation was the most common mutational types in this cohort of families.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Hereditary hemorrhagic telangiectasia resulted from a nonsense mutation Arg479 Stop in the ALK-1 gene].

OBJECTIVE: To identify the gene mutations in a pedigree with hereditary hemorrhagic telangiectasia. METHODS: Genomic DNA was extracted from the peripheral blood of the propositus. All of the exons, intron/exon boundaries and the 5' untranslation regions (UTR) of the ALK-1 and endoglin gene were amplified by polymerase chain reaction (PCR). The PCR products were screened by direct sequencing. RESULTS: The mutation is a C1437T substitution in exon 10 of the ALK-1 gene, resulting in Arg 479 Stop. CONCLUSION: The hereditary hemorrhagic telangiectasia propositus is caused by a heterozygous Arg 479 Stop mutation in the ALK-1 gene which has not been identified previously.

Activin Receptors, Type II↗
PubMed2001

Eight novel mutations of the FBN1 gene found in Japanese patients with Marfan syndrome.

Marfan syndrome (MFS), an autosomal dominant connective tissue disorder, is caused by mutations in the gene encoding fibrillin 1 (FBN1). The clinical spectrum and severity of MFS disorder varies greatly both between and within families. Since there have been only a few reports on the relationship between FBN1 genotypes and clinical phenotypes in Japanese patients, the FBN1 gene was analyzed in 27 Japanese patients diagnosed with MFS. The nucleotide sequence of the 65 exons of the FBN1 gene was analyzed by PCR and direct sequencing. We have identified six polymorphisms and nine mutations including: four missense mutations (C1652Y, Q2054P, D2127Y, C2221R) in six patients, three nonsense mutations (R215X, S813X, R2220X) in three patients, and two frameshift mutations (2567insT, 7790insT) in three patients. Six of these nine mutations were in the calcium-binding epidermal growth factor-like domains all causative mutations detected except for C2221R were novel. It has been reported that the severe phenotypes of infantile MFS correlate with mutations in the mid region of FBN1, however, mutations were not detected in this region in the population analyzed in this study. Our results suggest that the location of the mutation is not the sole determinant of phenotypic severity; rather there is some difference in the genetic basis of MFS between Japanese and Caucasian populations.

Adolescent↗
PubMed2003

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy.

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.

Alternative Splicing↗
PubMed2005

Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation.

Crigler-Najjar syndrome types I and II (CN1 and CN2) are usually inherited as autosomal recessive conditions and are characterized by non-hemolytic unconjugated hyperbilirubinaemia. CN1 is the most severe form, associated with the absence of hepatic bilirubin-uridinediphosphoglucuronate glucuronosyltransferase (UGT1A1) activity. CN2 presents intermediate levels of hyperbilirubinaemia as a result of an incomplete deficiency of hepatic UGT1A1 activity. Here, we present the analysis of UGT1A1 gene in 31 unrelated Crigler-Najjar (CN) syndrome patients. This analysis allowed us to identify 22 mutations, 12 of which were not previously described, expanding the spectrum of known UGT1 mutations to 77. Novel mutations, considered pathogenic, including one nonsense mutation, two altered splice sites, one single base deletion and nine missense mutations were identified in coding exons of the UGT1A1gene and flanking introns. Several novel missense mutations localize in critical domain of UGT1A1 enzyme. In addition, the evaluation of Gilbert-type promoter of UGT1A1in Crigler-Najjar (CN) syndrome patients was performed. The polymorphisms of the promoter region can modify the UGT1A1 mutation phenotype. This study represents the molecular characterization of the largest cohort of Italian Crigler-Najjar Gilbert syndrome patients studied so far; increase the mutational spectrum of UGT1A1 allelic variants worldwide and provide a new insight useful for clinical diagnosis and genetic counseling.

Alleles↗
PubMed2003

A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa.

Laminin-5 is the major adhesion ligand for epithelial cells. Mutations in the genes encoding laminin-5 cause junctional epidermolysis bullosa (JEB), a recessive inherited disease characterized by extensive epithelial-mesenchymal disadhesion. We describe a JEB patient compound heterozygote for two novel mutations in the gene (LAMA3) encoding the laminin alpha3 chain. The maternal mutation (1644delG) generates mRNA transcripts that undergo nonsense-mediated decay. The paternal mutation results in the Gly1506-->Glu substitution (G1506E) within the C-terminal globular region of the alpha3 chain (G domain). Mutation G1506E affects the proper folding of the fourth module of the G domain and results in the retention of most of the mutated polypeptide within the endoplasmic reticulum (ER). However, scant amounts of the mutated laminin-5 are secreted, undergo physiologic extracellular maturation, and correctly localize within the cutaneous basement membrane zone in patient's skin. Our findings represent the first demonstration of an ER-retained mutant laminin-5 leading to a mild JEB phenotype.

Adult↗
PubMed2001

A homozygous nonsense mutation in type XVII collagen gene (COL17A1) uncovers an alternatively spliced mRNA accounting for an unusually mild form of non-Herlitz junctional epidermolysis bullosa.

In this study we describe six Italian patients presenting an unusually mild variant of non-Herlitz junctional epidermolysis bullosa associated with a reduced expression of type XVII collagen. All patients are homozygous for a novel nonsense mutation (R795X) within exon 33 of COL17A1 and show a common haplotype, attesting propagation of an ancestral allele within the Italian population. Analysis of patients' COL17A1 transcripts showed the presence of two mRNA species: a normal-sized mRNA carrying mutation R795X that undergoes rapid decay, and a transcript generated by in-frame skipping of exon 33. Patients keratinocytes were shown to synthesize minute amounts of type XVII collagen, which appeared correctly localized along the cutaneous basement membrane. We therefore suggest that the exon 33-deleted COL17A1 splice variant encodes for type XVII collagen molecules that maintain a functional role and account for the mild phenotype of our patients.

Adult↗
PubMed2001

Diagnosis of Duchenne dystrophy by enhanced detection of small mutations.

OBJECTIVE: To determine whether detection of small mutations of the dystrophin gene can be increased using an enhanced method of single-strand conformation polymorphism analysis. BACKGROUND: Usual methods of DNA analysis for Duchenne dystrophy cannot identify mutations in one-third of cases. Muscle biopsy, with its inherent risks and added liability for patients with Duchenne dystrophy, becomes the sole method of diagnosis. Even with a tissue diagnosis of dystrophin deficiency, many families are excluded from carrier detection and prenatal diagnosis. METHODS: Genomic DNA from a cohort of 93 patients with Duchenne dystrophy without identifiable gene mutations was screened for mutations. In each case, 22 kilobases of genomic DNA were scanned, including all 79 exons of the dystrophin gene, adjacent intronic regions, and six alternative exons 1. RESULTS: Sixty-eight (73%) had small mutations, including 34 nonsense mutations, 27 microdeletions and insertions, and 7 splice site mutations. No missense mutations were found. One nonsense mutation in exon 59 was detected in four patients. Most mutations were new; 54 of 62 different small mutations have not been reported. Mutations were found throughout the gene: 24% in the first quartile, 31% in the second, 16% in the third, and 29% in the fourth. CONCLUSIONS: A highly sensitive single-strand conformation polymorphism method substantially increased detection of small dystrophin gene mutations and made it possible to diagnose approximately 90% of patients with Duchenne dystrophy by DNA analysis. These findings, combined with cost savings and safety issues, provide compelling reasons to consider DNA analysis as the initial diagnostic test for the suspected dystrophin-deficient patient.

Adolescent↗
PubMed2004

[X-linked adrenoleukodystrophy ABCD1 gene mutation analysis in China].

OBJECTIVE: To investigate mutations of ABCD1 gene in X- linked adrenoleukodystrophy (ALD) patients in China. METHODS: Polymerase chain reaction and DNA direct sequencing were employed to analyze the 10 exons of ABCD1 gene in 25 ALD patients. RESULTS: Seventeen mutations in different exons (except exons 4, 9 and 10) were identified in 18 of 25 patients. Most of the mutations were missense mutations, including R182P, G266R, H283D, S404P, N509I, R518G, L520Q, Q556R, S606L and R617C, four (H283D, S40 4P, N509I, R518G) of 10 missense mutations were novel. Also identified were 3 nonsense mutations (W132X, W242X, W595X), 1 dinucleotides deletion mutation (1414 del AG) resulting in frameshift, and 1 base pair deletion at splice acceptor site (IVS5-6 del C). Two synonymous mutations (L516L and V349V) appeared simultaneously in 2 unrelated patients, and no other mutations could be found with them in all 10 exons screened. CONCLUSION: There were no hot spot mutations in ABCD1 gene in China. Mutations in gene were found over 70% of patients with ALD in China. The ABCD1 gene mutations identified revealed no obvious correlation between the type of mutation and phenotype.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2002

Novel PEX1 mutations and genotype-phenotype correlations in Australasian peroxisome biogenesis disorder patients.

The peroxisome biogenesis disorders (PBDs) are a group of neuronal migration/neurodegenerative disorders that arise from defects in PEX genes. A major subgroup of the PBDs includes Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). These three disorders represent a clinical continuum with Zellweger syndrome the most severe. Mutations in the PEX1 gene, which encodes a protein of the AAA ATPase family involved in peroxisome matrix protein import, account for the genetic defect in more than half of the patients in this PBD subgroup. We report here on the results of PEX1 mutation detection in an Australasian cohort of PEX1-deficient PBD patients. This screen has identified five novel mutations, including nonsense mutations in exons 14 and 19 and single nucleotide deletions in exons 5 and 18. Significantly, the allele carrying the exon 18 frameshift mutation is present at moderately high frequency (approx. 10%) in this patient cohort. The fifth mutation is a missense mutation (R798G) that attenuates, but does not abolish PEX1 function. We have evaluated the cellular impact of these novel mutations, along with that of the two most common PEX1 mutations (c.2097-2098insT and G843D), in PBD patients by determining the levels of PEX1 mRNA, PEX1 protein, and peroxisome protein import. The findings are consistent with a close correlation between cellular phenotype, disease severity, and PEX1 genotype.

ATPases Associated with Diverse Cellular Activitie↗