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PubMed2001

Characterization of mutant neutrophil elastase in severe congenital neutropenia.

Severe congenital neutropenia is a heritable human disorder characterized by neutropenia and acute myelogenous leukemia. We recently determined that the majority of cases result from de novo or autosomal dominantly inherited heterozygous mutations in ELA2, encoding neutrophil elastase. Neutrophil elastase is a chymotryptic serine protease localized in granules of neutrophils and monocytes and is the major target of inhibition of the serpin alpha(1)-antitrypsin. The mutations causing severe congenital neutropenia consist of amino acid missense substitutions, in-frame deletion, splice donor mutation producing a deletion, splice acceptor mutation causing insertion of novel residues, and protein truncating mutations of the carboxyl terminus resulting from nonsense substitutions and deletions leading to frameshifts. We have expressed 14 mutant forms of neutrophil elastase in vitro and have characterized their biochemical properties. The mutations have variable effects on proteolytic activity, eliminating the possibility that the disease results from haploinsufficiency. There is no evidence that the mutant enzymes are cytotoxic. The mutant enzymes retain vulnerability to inhibition by alpha(1)-antitrypsin, but demonstrate variable avidity for interaction with this serpin. Somewhat surprisingly, the mutant enzymes inhibit the wild type enzyme when both are coexpressed within the same cell, suggesting the potential to interfere with normal subcellular trafficking or post-translational processing.

Animals↗
PubMed2001

A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral motor and sensory neuropathies characterized by chronic distal weakness with progressive muscular atrophy and sensory loss in the distal extremities. Inheritance can be autosomal dominant, X-linked or autosomal recessive (ARCMT). Recently, a locus responsible for a demyelinating form of ARCMT disease, named CMT4F, has been mapped on 19q13 in a large consanguineous Lebanese family. L- and S-periaxin are proteins of myelinating Schwann cells and homozygous periaxin-null mice display extensive demyelination of myelinated fibers in the peripheral nervous system, which suggests that the periaxin gene is a good candidate gene for an ARCMT disease. The human gene encoding the periaxins (PRX) was mapped to 19q13, in the CMT4F candidate interval. After characterizing the human PRX gene, we identified a nonsense R196X mutation in the Lebanese family which cosegregated with CMT. Histopathological and immunohistochemical analysis of a sural nerve biopsy of one patient revealed common features with the mouse mutant and the absence of L-periaxin from the myelin sheath. These data confirm the importance of the periaxin proteins to normal Schwann cell function and substantiate the utility of the periaxin-null mouse as a model of ARCMT disease.

Amino Acid Sequence↗
PubMed2005

Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR.

PURPOSE: Norrie disease (OMIM 310600) is a rare X-linked disorder characterized by congenital blindness in males. Approximately 40 to 50% of the cases develop deafness and mental retardation. X-linked familial exudative vitreoretinopathy (XL-FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Both X-linked disorders are due to mutations in the NDP gene, which encodes a 133 amino acid protein called Norrin, but autosomal recessive (AR) and autosomal dominant (AD) forms of FEVR have also been described. In this study, we report the molecular findings and the related phenotype in five Spanish families affected with Norrie disease or XL-FEVR due to mutations of the NDP gene. METHODS: The study was conducted in 45 subjects from five Spanish families. These families were clinically diagnosed with Norrie disease or similar conditions. The three exons of the NDP gene were analyzed by automatic DNA sequencing. Haplotype analyses were also performed. RESULTS: Two new nonsense mutations, apart from other mutations previously described in the NDP gene, were found in those patients affected with ND or X-linked FEVR. CONCLUSIONS: An important genotype-phenotype variation was found in relation to the different mutations of the NDP gene. In fact, the same mutation may be responsible for different phenotypes. We speculate that there might be other molecular factors that interact in the retina with Norrin, which contribute to the resultant phenotypes.

Adolescent↗
PubMed2002

A previously undescribed nonsense mutation of the HFE gene.

A patient with clinically manifest hereditary hemochromatosis was found to be heterozygous for the c.845 A-->G (C282Y) mutation. As simple heterozygotes for this mutation do not develop the hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed nonsense mutation was identified at c.211 C-->T (R74X). The patient's brother who also had the hemochromatosis phenotype shared his HFE genotype. To determine how common such mutations might be, the coding and 5' region of the HFE genes of 11 subjects who had been found in a large population survey to be heterozygous for the C282Y mutation and had elevated ferritin levels were sequenced. No mutations were found. Sequencing of the HFE gene also revealed two polymorphisms that had not previously been noted, -467 C-->G and -970 T-->G. Neither of these mutations appear to cause an abnormality in iron metabolism.

Codon, Nonsense↗
PubMed2005

AMPD1 C34T mutation selectively affects AMP-deaminase activity in the human heart.

Possession of the nonsense mutation in AMPD 1 C34T gene has been linked to improved survival in patients with heart failure, possibly by promoting the formation of adenosine. This mutation is known to decrease the activity of AMP-deaminase in skeletal muscle. We have found that the AMPD1 mutation decreases the activity of AMP-deaminase in the heart without changing the activity of any other enzymes of adenine nucleotide metabolism. Protective mechanism of this mutation may be thus induced by local cardiac metabolic changes.

AMP Deaminase↗
PubMed2006

Mutations in the gene KCNV2 encoding a voltage-gated potassium channel subunit cause "cone dystrophy with supernormal rod electroretinogram" in humans.

"Cone dystrophy with supernormal rod electroretinogram (ERG)" is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. We have linked the disorder to a 0.98-cM (1.5-Mb) region on chromosome 9p24, flanked by rs1112534 and rs1074449, using homozygosity mapping in one large consanguineous pedigree. Analysis of one gene within this region, KCNV2, showed a homozygous nonsense mutation. Mutations were also found in 17 alleles of 10 other unrelated families with the same disorder. In situ hybridization demonstrated KCNV2 expression in human rod and cone photoreceptors. The precise function of KCNV2 in human photoreceptors remains to be determined, although this work suggests that mutations might perturb or abrogate I(KX), the potassium current within vertebrate photoreceptor inner segments, which has been shown to set their resting potential and voltage response.

Chromosomes, Human, Pair 9↗
PubMed2005

Molecular genetic analysis of SLC3A1 and SLC7A9 genes in Czech and Slovak cystinuric patients.

Cystinuria is a frequently inherited metabolic disorder in the Czech population (frequency 1/5,600) caused by a defect in the renal transport of cystine and dibasic amino acids (arginine, lysine and ornithine). The disease is characterized by increased urinary excretion of the amino acids and often leads to recurrent nephrolithiasis. Cystinuria is classified into two subtypes (type I and type non-I). Type I is caused predominantly by mutations in the SLC3A1 gene (2p16.3), encoding heavy subunit (rBAT) of the heterodimeric transporter. Cystinuria non-I type is caused by mutations in the SLC7A9 gene (19q13.1). In this study, we present results of molecular genetic analysis of the SLC3A1 and the SLC7A9 genes in 24 unrelated cystinuria families. Individual exons of the SLC3A1 and SLC7A9 genes were analyzed by direct sequencing. We found ten different mutations in the SLC3A1 gene including six novel ones: three missense mutations (G140R), D179Y and R365P), one splice site mutation (1137-2A>G), one deletion (1515_1516delAA), and one nonsense mutation (Q119X). The most frequent mutation, M467T; was detected in 36% of all type I classified alleles. In the SLC7A9 gene we found six mutations including three new ones: one missense mutation (G319R), one insertion (611_612insA) and one deletion (205_206delTG). One patient was compound heterozygote for one SLC3A1 and one SLC7A9 mutation. Our results confirm that cystinuria is a heterogeneous disorder at the molecular level, and contribute to the understanding of the distribution and frequency of mutations causing cystinuria in the Caucasian population.

Adolescent↗
PubMed2004

A novel nonsense mutation of the mineralocorticoid receptor gene in a Swedish family with pseudohypoaldosteronism type I (PHA1).

Pseudohypoaldosteronism type I (PHA1) is a condition associated with salt wasting leading to dehydration, hypotension, hyperkalemia, and metabolic acidosis. Sporadic cases and two familial forms, one autosomal dominant and one autosomal recessive form, have been described. The autosomal dominant or sporadic form manifests milder salt wasting that remits with age. Mutations in the gene encoding the mineralocorticoid receptor (MR) have been identified in patients with the autosomal dominant inheritance. However, recent studies suggest that the autosomal dominant and sporadic forms are genetically heterogeneous and that additional genes might be involved. We report on the study of 15 members of a Swedish five-generation family with the autosomal dominant form of PHA1. Interestingly, neuropathy was found in two of five affected individuals. A novel heterozygous nonsense mutation C436X in exon 2 was identified in the index patient by linkage analysis, PCR, and direct sequencing of the MR gene. Analysis of the family demonstrated that the mutation segregated with PHA1 in the family. It is unclear whether the neuropathy is associated with the mutation found. Our results together with previously published data suggest that loss-of-function mutations of the MR gene located at 4q31.1, commonly are associated with the autosomal dominant form of PHA1.

Adult↗
PubMed2005

Oligophrenin 1 mutations frequently cause X-linked mental retardation with cerebellar hypoplasia.

BACKGROUND: Mutations of oligophrenin 1, one of the first genes identified in nonspecific X-linked mental retardation (MRX), have been described in patients with moderate to severe cognitive impairment and predominant cerebellar hypoplasia, in the vermis. OBJECTIVE: To further delineate the phenotypic and mutational spectrum of the syndrome, by screening oligophrenin 1 in two cohorts of male patients with mental retardation (MR) with or without known posterior fossa anomalies. METHODS: Clinical examination, cognitive testing, MRI studies, and mutational analysis (denaturing gradient gel electrophoresis and direct sequencing) on blood lymphocytes were performed in 213 unrelated affected individuals: 196 patients classified as MRX and 17 patients with MR and previously detected cerebellar anomalies. RESULTS: Four novel oligophrenin 1 mutations were identified. In the MRX group, two nonsense mutations were detected. In the MR group, two mutations were found: a deletion of exons 16 to 17 and a splice site mutation. All patients shared characteristic clinical, radiologic, and distinctive features with a degree of intrafamilial variability in motor and cognitive deficits. CONCLUSIONS: Oligophrenin 1 mutations were found in 12% (2/17) of individuals with mental retardatin and known cerebellar anomalies and in 1% (2/196) of the X-linked mental retardation group.

Adolescent↗
PubMed2005

Identification of a splicing enhancer in MLH1 using COMPARE, a new assay for determination of relative RNA splicing efficiencies.

Exonic splicing enhancers (ESEs) are sequences that facilitate recognition of splice sites and prevent exon-skipping. Because ESEs are often embedded within protein-coding sequences, alterations in them can also often be interpreted as nonsense, missense or silent mutations. To correctly interpret exonic mutations and their roles in diseases, it is important to develop strategies that identify ESE mutations. Potential ESEs can be found computationally in many exons but it has proven difficult to predict whether a given mutation will have effects on splicing based on sequence alone. Here, we describe a flexible in vitro method that can be used to functionally compare the effects of multiple sequence variants on ESE activity in a single in vitro splicing reaction. We have applied this method in parallel with conventional splicing assays to test for a splicing enhancer in exon 17 of the human MLH1 gene. Point mutations associated with hereditary non-polyposis colorectal cancer (HNPCC) have previously been found to correlate with exon-skipping in both lymphocytes and tumors from patients. We show that sequences from this exon can replace an ESE from the mouse IgM gene to support RNA splicing in HeLa nuclear extracts. ESE activity was reduced by HNPCC point mutations in codon 659, indicating that their primary effect is on splicing. Surprisingly, the strongest enhancer function mapped to a different region of the exon upstream of this codon. Together, our results indicate that HNPCC point mutations in codon 659 affect an auxillary element that augments the enhancer function to ensure exon inclusion.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype.

We report the results of genetic analysis on a series of 51 patients attending this Haemophilia Comprehensive Care Centre. The most common cause of severe haemophilia A--the factor VIII intron 22 inversion was detected in eight families and the factor VIII intron 1 inversion in three families. Mutation analysis was carried out on the remaining patients by nucleotide sequencing of genomic DNA after screening with conformation-sensitive gel electrophoresis (CSGE) or denaturing high-performance liquid chromatography (dHPLC). A total of 27 different FVIII non-inversion mutations were detected. Severe haemophilia was associated with 12 null mutations (six nonsense, six frameshift) and four missense mutations. A further 11 different missense mutations were associated with moderate or mild disease. To our knowledge, six null mutations [1950del 4(tttg), 3270-75insA, 4416del 10, 6735-38delA, W1029X, Y1792X] and four missense mutations (E1682K, M1947V, P2048L, P2143L) have not been previously published. Each novel missense mutation occurred at a highly conserved residue, no other candidate mutation was detected on screening the entire coding region of the FVIII gene and they were not detected in a screen of individuals without haemophilia A. The genotype-phenotype correlations of the FVIII mutations detected will be discussed.

Base Sequence↗
PubMed2005

Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

Codon, Nonsense↗
PubMed2001

Identification of three novel mutations in the USH1C gene and detection of thirty-one polymorphisms used for haplotype analysis.

Usher syndrome (USH) is a clinically and genetically heterogeneous autosomal recessive disorder in which sensorineural hearing loss is associated with retinitis pigmentosa. Usher syndrome type 1, the most severe form, is characterized by profound congenital deafness, vestibular dysfunction, and prepubertal onset of retinitis pigmentosa. Six different USH1 genes have so far been mapped, of which two have already been identified. MYO7A, encoding the unconventional myosin VIIA, underlies USH1B. Recently, the USH1C gene was shown to encode harmonin, a PDZ domain-containing protein. A previous screening of 18 unrelated USH1 patients, without a detected MYO7A mutation, for the three USH1C mutations described to date had demonstrated the presence of the 238-239insC mutation in the heterozygous state in four of them. A complete USH1C mutation screening in these four carriers of the 238-239insC mutation resulted in the detection of the second mutation in all the individuals, and the identification of three novel mutations, namely two splice site mutations (IVS1+1G>T and IVS5+1G>A) and a nonsense mutation (R31X). Thirty-one polymorphisms were detected in the USH1C gene. We observed that the E519D substitution is non-pathogenic, which is of particular interest for molecular diagnosis. Our analysis indicated that all the carriers of the 238-239insC mutation share a common haplotype. A different common haplotype was found in the two IVS1+1G>T carriers. Future studies of additional carriers and non-carriers should document the here proposed founder effect of these two mutations.

Abnormalities, Multiple↗
PubMed2005

A mutation in the dimerization domain of filamin c causes a novel type of autosomal dominant myofibrillar myopathy.

Myofibrillar myopathy (MFM) is a human disease that is characterized by focal myofibrillar destruction and pathological cytoplasmic protein aggregations. In an extended German pedigree with a novel form of MFM characterized by clinical features of a limb-girdle myopathy and morphological features of MFM, we identified a co-segregating, heterozygous nonsense mutation (8130G-->A; W2710X) in the filamin c gene (FLNC) on chromosome 7q32.1. The mutation is the first found in FLNC and is localized in the dimerization domain of filamin c. Functional studies showed that, in the truncated mutant protein, this domain has a disturbed secondary structure that leads to the inability to dimerize properly. As a consequence of this malfunction, the muscle fibers of our patients display massive cytoplasmic aggregates containing filamin c and several Z-disk-associated and sarcolemmal proteins.

Base Sequence↗
PubMed2007

Gastric carcinoid: germline and somatic mutation of the neurofibromatosis type 1 gene.

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited conditions. A range of complications has been described, including gastrointestinal manifestations. Gastric carcinoid tumours are associated with multiple endocrine neoplasia, atrophic gastritis and pernicious anaemia but have not been reported in NF1 in the absence of other predisposing factors. We report the occurrence and investigation of a gastric carcinoid tumour in a 23-year-old woman with previously uncomplicated NF1. Analysis of the tumour tissue revealed loss of heterozygosity at the NF1 gene locus but a normal karyotype and an absence of microsatellite instability. A germline NF1 gene nonsense mutation in exon 37 was detected by denaturing high-performance liquid chromatography and DNA sequence analysis. This is the first reported occurrence of a gastric carcinoid tumour in a patient with NF1 in the absence of other predisposing factors such as pernicious anaemia. The analyses indicate that the carcinoid arose through NF1 gene inactivation but in the absence of an inherited NF1 gene microdeletion. This case adds to the range of gastrointestinal tumours that may be encountered in patients with NF1, particularly in those who present with upper gastrointestinal haemorrhage.

Adult↗
PubMed2002

A nonsense mutation in the enamelin gene causes local hypoplastic autosomal dominant amelogenesis imperfecta (AIH2).

Amelogenesis imperfecta (AI) is an inherited tooth disorder affecting tooth enamel formation only. A gene for autosomal dominant AI, the local hypoplastic form, has been localized to a 4 Mb region on chromosome 4q (AIH2). The enamelin gene (ENAM ), has been mapped to chromosome 4q21, to the same region as AIH2, and was recently shown to be mutated in patients with smooth and thin hypoplastic autosomal dominant AI (ADAI). In this study, we describe an ENAM mutation causing the local hypoplastic form of ADAI, a phenotype that accounts for 27% of the autosomally inherited cases in Northern Sweden. This nonsense mutation in the enamelin gene results in a truncated peptide of 52 amino acids as compared with 1142 amino acids of the normal protein. Our results show that while a splice site mutation is associated with smooth and thin hypoplastic AI, a base substitution resulting in a shorter peptide causes local hypoplasia of the enamel, a milder form of AI. These findings support ENAM as a disease gene, and shed new light on the molecular mechanism of the disease and to the function of the enamelin protein in enamel formation.

Amelogenesis Imperfecta↗
PubMed2005

An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.

CONTEXT: PROP1 gene mutations are usually associated with childhood onset GH and TSH deficiencies, whereas gonadotroph deficiency is diagnosed at pubertal age. OBJECTIVES: We report a novel PROP1 mutation revealed by familial normosmic hypogonadotropic hypogonadism. We performed in vitro transactivation and DNA binding experiments to study functional consequences of this mutation. SETTING: Three brothers were followed in the Department of Endocrinology of a French university hospital. PATIENTS: These patients from a consanguineous kindred were referred for cryptorchidism and/or delayed puberty. RESULTS: Initial investigations revealed hypogonadotropic hypogonadism. One of the patients had psychomotor retardation, intracranial hypertension, and minor renal malformations. The brothers reached normal adult height and developed GH and TSH deficiencies after age 30. A novel homozygous nonsense mutation (W194X) was found in the PROP1 gene, indicating that the protein is truncated in its transactivation domain. Transfection studies confirmed the deleterious effect of this mutation, whose transactivation capacity was only 34.4% of that of the wild-type. Unexpectedly altered DNA-binding properties suggested that the C-terminal end of the factor plays a role in protein-DNA interaction. CONCLUSIONS: PROP1 mutations should be considered among the growing number of genetic causes of initially isolated hypogonadotropic hypogonadism. This report extends the phenotype variability associated with PROP1 mutations.

Adult↗
PubMed2001

No evidence of accelerated atherosclerosis in a 66-yr-old chylomicronemia patient homozygous for the nonsense mutation (Tyr61-->stop) in the lipoprotein lipase gene.

Whether chylomicronemia is atherogenic or not has yet to be determined in humans. We investigated a 66-yr-old female with severe chylomicronemia resulting from a lipoprotein lipase (LPL) deficiency. The patient's plasma triglyceride level was approximately 2000 mg/dl. Both LPL activity and the mass of postheparin plasma in this patient were virtually absent. A nonsense mutation in exon 3 (Tyr61-->Stop) was identified in the patient's LPL gene, and a restriction fragment length polymorphism analysis established that the patient was homozygous for this mutation. The patient was neither a diabetic nor a smoker. Clinically, the patient had never experienced pancreatitis or angia pectoris. An examination of her carotid, femoral and coronary arteries by ultrasonogram and electrocardiogram after exercise-tolerance testing showed no accelerated atherosclerosis. This case suggests that atherosclerosis may not occur despite massive hyperlipidemia, when LPL bridging was not present due to the absence of LPL secretion and circulating mass.

Aged↗