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PubMed2005

Identification of novel RPGR ORF15 mutations in X-linked progressive cone-rod dystrophy (XLCORD) families.

PURPOSE: To test the incidence of mutations in RPGR ORF15 in six families with X-linked progressive retinal degeneration (cone-rod dystrophy [XLCORD], macular or cone dystrophy) and to undertake a detailed phenotypic assessment of families in whom ORF15 mutations were identified. METHODS: To amplify and sequence ORF15 in its entirety, a cloning strategy was developed. Families with mutations in ORF15 underwent electrophysiological testing, color vision assessment, color fundus photography, and fundus autofluorescence (AF) imaging. RESULTS: Novel protein truncation mutations were identified in two families. In family A, a 2-bp mutation was identified in ORF15+A1094C G1095T, predicted to result in a truncated protein (E364D/E365X). In family B, a G-to-T transversion (ORF15+1176G>T) resulted in a nonsense mutation (G392X). Characteristics of phenotype in both families included progressive deterioration of central vision and subsequently night vision, mild photophobia, and moderate to high myopia. Ophthalmoscopic abnormalities were generally confined to the macula. A parafoveal ring of increased AF was observed, and electrophysiological evidence of a greater generalized abnormality in cone than rod responses were consistent with a cone-rod dystrophy phenotype. CONCLUSIONS: The cloning strategy for ORF15 facilitated comprehensive sequence analysis in patients. Two families were identified with nonsense mutations, and clinical evaluation revealed them both to have a similar phenotype. The presence of a parafoveal ring of increased AF was an early indicator of affected status in these families. No disease-causing mutations in ORF15 were detected in four other families, suggesting that ORF15 mutations may not be the most common cause of XLCORD.

Adult↗
PubMed2006

Peroxisomal proliferator activated receptor-gamma deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3).

BACKGROUND: Familial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-gamma. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. METHODS: We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. RESULTS: The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. CONCLUSION: Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-gamma deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

Canada↗
PubMed2006

The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients.

Disease-causing alterations within the F8 gene were identified in 177 hemophilia A families of Portuguese origin. The spectrum of non-inversion F8 mutations in 101 families included 67 different alterations, namely: 36 missense, 8 nonsense and 4 splice site mutations, as well as 19 insertions/deletions. Thirty-four of these mutations are novel. Molecular modeling allowed prediction of the conformational changes introduced by selected amino acid substitutions and their correlation with the patients' phenotypes. The relatively frequent, population-specific, missense mutations together with de novo alterations can lead to significant differences in the spectrum of F8 mutations among different populations.

Alternative Splicing↗
PubMed2000

Antisense oligonucleotides against protein kinase CK2-alpha inhibit growth of squamous cell carcinoma of the head and neck in vitro.

BACKGROUND: Human squamous cell carcinomas of the head and neck (SCCHN) overexpress the protein kinase CK2, and elevated CK2 activity correlates with aggressive tumor behavior and poor clinical outcome. We therefore investigated whether interference with CK2 expression would inhibit SCCHN cell growth in vitro. METHODS: We targeted the catalytic (alpha) subunit of CK2 using an antisense oligodeoxynucleotide (ODN) strategy. Human Ca9-22 cells derived from SCCHN were transfected with CK2-alpha sense, nonsense, or antisense ODN; CK2 activity was measured; and the effect on CK2 activity and on cell growth was determined. RESULTS: Transfection of Ca9-22 cells with antisense CK2-alpha ODN resulted in significantly decreased CK2 kinase activity associated with nuclear chromatin and in dose-dependent growth inhibition of Ca9-22 cells in vitro. CONCLUSIONS: Interference with the protein kinase CK2 signal in SCCHN cells may offer a novel anticancer strategy for this malignancy.

Base Sequence↗
PubMed2005

Molecular characterization of Italian nevoid basal cell carcinoma syndrome patients.

Mutations in the PTCH gene, the human homolog of the Drosophila patched gene, have been found to lead to the autosomal dominant disorder termed Nevoid Basal Cell Carcinoma Syndrome (NBCCS, also called Gorlin Syndrome). Patients display an array of developmental anomalies and are prone to develop a variety of tumors, with multiple Basal Cell Carcinomas occurring frequently. We provide here the results of molecular testing of a set of Italian Nevoid Basal Cell Carcinoma Syndrome patients. Twelve familial patients belonging to 7 kindreds and 5 unaffected family members, 6 non-familial patients and an additional set of 7 patients with multiple Basal Cell Carcinoma but no other criteria for the disease were examined for mutations in the PTCH gene. All of the Nevoid Basal Cell Carcinoma Syndrome patients were found to carry variants of the PTCH gene. We detected nine novel mutations (1 of which occurring twice): 1 missense mutation (c.1436T>G [p.L479R]), 1 nonsense mutation (c.1138G>T [p.E380X]), 6 frameshift mutations (c.323_324ins2, c.2011_2012dup, c.2535_2536dup, c.2577_2583del, c.3000_3005del, c.3050_3051del), 1 novel splicing variant (c.6552A>T) and 3 mutations that have been previously reported (c.3168+5G>A, c.1526G>T [p.G509V], and c.3499G>A [p.G1167R]). None of the patients with multiple Basal Cell Carcinoma but no other criteria for the syndrome, carried germline coding region mutations.

Adolescent↗
PubMed2006

GS3, a major QTL for grain length and weight and minor QTL for grain width and thickness in rice, encodes a putative transmembrane protein.

The GS3 locus located in the pericentromeric region of rice chromosome 3 has been frequently identified as a major QTL for both grain weight (a yield trait) and grain length (a quality trait) in the literature. Near isogenic lines of GS3 were developed by successive crossing and backcrossing Minghui 63 (large grain) with Chuan 7 (small grain), using Minghui 63 as the recurrent parent. Analysis of a random subpopulation of 201 individuals from the BC3F2 progeny confirmed that the GS3 locus explained 80-90% of the variation for grain weight and length in this population. In addition, this locus was resolved as a minor QTL for grain width and thickness. Using 1,384 individuals with recessive phenotype (large grain) from a total of 5,740 BC3F2 plants and 11 molecular markers based on sequence information, GS3 was mapped to a DNA fragment approximately 7.9 kb in length. A full-length cDNA corresponding to the target region was identified, which provided complete sequence information for the GS3 candidate. This gene consists of five exons and encodes 232 amino acids with a putative PEBP-like domain, a transmembrane region, a putative TNFR/NGFR family cysteine-rich domain and a VWFC module. Comparative sequencing analysis identified a nonsense mutation, shared among all the large-grain varieties tested in comparison with the small grain varieties, in the second exon of the putative GS3 gene. This mutation causes a 178-aa truncation in the C-terminus of the predicted protein, suggesting that GS3 may function as a negative regulator for grain size. Cloning of such a gene provided the opportunity for fully characterizing the regulatory mechanism and related processes during grain development.

Amino Acid Sequence↗
PubMed2003

Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation.

BACKGROUND/AIMS: Progressive familial intrahepatic cholestasis characterized by normal serum gamma-glutamyltransferase activity can be due to mutations in familial intrahepatic cholestasis type 1 (FIC1) (ATP8B1), a gene expressed in several organs. In some cases, it is associated with extrahepatic features. We searched for FIC1 mutations and analyzed the outcome of extrahepatic features after liver transplantation in two children with this form of progressive familial intrahepatic cholestasis associated with chronic unexplained diarrhea and short stature. METHODS: FIC1 sequence was determined after polymerase chain reaction (PCR) of genomic lymphocyte DNA and/or reverse transcription-PCR of liver or lymphocyte RNA. RESULTS: A homozygous amino acid change deletion was found in one child. The second child harboured compound heterozygous missense and nonsense mutations. In both children, despite successful liver transplantation, evolution (follow-up: 9.5-11 years) was characterized by exacerbation of diarrhea and no catch-up of stature growth, and appearance of liver steatosis. CONCLUSIONS: Progressive familial intrahepatic cholestasis characterized by normal serum gamma-glutamyltransferase activity and extrahepatic features corresponds to progressive familial intrahepatic cholestasis type 1. Extrahepatic symptomatology is not corrected or may be aggravated by liver transplantation, impairing life quality.

Adenosine Triphosphatases↗
PubMed2001

Identification of novel C253Y missense and Y864X nonsense mutations in the insulin receptor gene in type A insulin-resistant patients.

Mutations in the insulin receptor gene have been reported in cases of type A insulin resistance. We report herein two cases of type A insulin resistance, which involve some novel mutations. Case 1 is a heterozygote of the C253Y missense mutation and case 2 is a heterozygote of the Y864X nonsense mutation. In the C253Y missense mutation in exon 3, a cysteine residue is replaced with tyrosine in the cysteine-rich domain of the alpha subunit. The Y864X in exon 13 results in a truncated receptor, which is devoid of most of the beta subunit. This mutant receptor could not be expressed on a cell membrane since the transmembrane domain is missing. Other significant mutations were not found for the entire coding regions and splice/donor sites.

Adolescent↗
PubMed2004

Arg120stop nonsense mutation in the RP2 gene: mutational hotspot and germ line mosaicism?

Mutations in the RP2 gene account for up to 20% of X-linked recessive retinitis pigmentosa (RP). Arg120stop is to date the most frequently reported mutation found in RP2. Mutation screening was performed during the course of a large screening program of retinal degenerative disorders (RDDs) in South Africa using exon 1 and 2 of RP2 in 20 unrelated families with an X-linked mode of retinal degenerative inheritance. Direct sequencing analysis revealed a C-->T transition at position 358 in the proband in a family of German origin. Subsequent analysis revealed that this Arg120stop mutation cosegregated with the disease in an additional affected family member. The nonsense mutation, Arg120stop, could not however, be detected in the somatic cells of the obligate carrier female. This, the first report of a germ line mutation for a family with RP, has many implications for genetic counseling of retinal degeneration (RD). To avoid inaccurate risk assessment for RP due to epigenetic events, such as the rare occurrence of germ line mosaicism, genetic counseling in families with XLRP should always be guided by molecular testing.

Adult↗
PubMed1994

[Mutations of RET proto-oncogene in Hirschsprung disease].

Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. Recently, a gene for HSCR has been mapped to chromosome 10q11.2. No recombination was observed between the disease locus and the locus for the RET proto-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. Here we report on nonsense and missense mutations in the extracellular domain of the RET protein (exons 2, 3, 5 and 6) in 6 unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A). Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

Codon, Nonsense↗
PubMed2005

Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene.

Methylmalonyl-CoA mutase (MCM) apoenzyme deficiency is a rare metabolic disease that may result in distinct biochemical phenotypes of methylmalonic acidemia (MMA), namely mut(o) and mut-. We analyzed a cohort of 40 MCM-deficient patients with MMA affected by either the mut(o) or the mut- form of the disease. By direct sequencing of cDNA and gDNA of the MUT gene, we detected 42 mutations, 29 of which were novel mutations. These included five frameshift mutations (insertion, deletion, or duplication of a single nucleotide), five sequence modifications in consensus splice sites, six nonsense and 12 missense mutations, and a large genomic deletion including exon 12. We explored how the 12 novel missense mutations might cause the observed phenotype by mapping them onto a three-dimensional model of the human MCM generated by homology with the P. shermanii enzyme. In this work we update the spectrum of MCM mutations (n=84), and then discuss their prevalence and distribution throughout the coding sequence in relation to the enzyme structure.

Amino Acid Metabolism, Inborn Errors↗
PubMed2006

Homozygous null mutations in the ABCA4 gene in two families with autosomal recessive retinal dystrophy.

PURPOSE: To identify the genes causing autosomal recessive retinal dystrophy in Indian families and to characterize the associated phenotypes. DESIGN: Experimental and observational. METHODS: Families with autosomal recessive nonsyndromic retinal dystrophies were recruited. Complete ophthalmic evaluation, including visual acuity, visual fields, fundus examinations, and electroretinography, was performed on all members. Genotyping of 14 families for two or more microsatellite markers flanking each of 21 different genes causing retinal dystrophy was done by standard methods to screen for the presence of homozygosity by descent. Mutational screening of the ABCA4 gene was carried out on 18 members (five affected) of two families by amplification and direct automated sequencing of exons and flanking sequences. Sequence alterations identified were tested for cosegregation with disease in the families and for presence in 100 unrelated normal controls. RESULTS: Two of 14 families showed homozygosity shared by affected individuals for markers flanking the ABCA4 locus. A homozygous nonsense mutation in the ABCA4 gene of Arg2030Stop was found in one family and a homozygous single base deletion leading to frameshift at Arg409 was found in the second family. Both of these mutations were found to cosegregate with disease. Five affected individuals from the two families had early-onset visual loss, diminished rod and cone electroretinographic responses, and widespread atrophy of the retinal pigment epithelium. CONCLUSION: Homozygous null mutations in ABCA4 produced a severe widespread retinal degeneration that showed marked central retinal involvement.

ATP-Binding Cassette Transporters↗
PubMed2005

Two novel CHS1 (LYST) mutations: clinical correlations in an infant with Chediak-Higashi syndrome.

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease characterized by variable degrees of oculocutaneous albinism, recurrent infections, and a mild bleeding tendency, with late neurologic dysfunction. Most patients also undergo an accelerated phase of lymphohistiocytosis and die at an early age unless they receive an allogeneic hematopoietic stem cell transplant (SCT). Mutations in the CHS1 (LYST) gene result in CHS. Here, we describe an adopted infant who is compound heterozygous for two novel CHS1 gene mutations, both of which are predicted to result in truncated proteins. The two mutations are a nonsense mutation (c.1540 C>T, CGA>TGA, R514X) in exon 5 and a one base pair deletion (del c.9893T, F3298fsX3304) in exon 43, coding for part of the CHS1 protein's BEACH domain. These two newly described mutations are expected to give rise to a severe phenotype and, indeed, the patient had absolutely no cytotoxicity by natural killer cells or cytotoxic lymphocytes prior to his allogeneic SCT.

Blood Platelets↗
PubMed2002

Molecular genetic study of myophosphorylase deficiency (McArdle's disease) in two Yemenite-Jewish families.

Using direct sequencing and restriction fragment length polymorphism analysis, we identified two novel mutations in two unrelated Yemenite-Jewish families with typical symptoms of McArdle's disease. In one family, both father and daughter were affected, an example of pseudo-dominant transmission. The daughter was a compound heterozygote for a new nonsense mutation (R207X) and a new missense mutation (R602Q) while her father was homozygous for the R207X mutation. The mother carried only the R602Q mutation and was an asymptomatic heterozygote. In the second family, the only affected member was homozygous for the R207X mutation. This first molecular genetic study of McArdle's disease in Yemenite-Jewish patients expands the already remarkable genetic heterogeneity of McArdle's disease and suggests the existence of ethnic or private mutations within this group.

Adult↗
PubMed2001

Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

BACKGROUND: The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy. METHODS AND RESULTS: Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family. CONCLUSIONS: Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.

Adult↗
PubMed2003

IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation.

BACKGROUND: Approximately 10 percent of infants with intrauterine growth retardation remain small, and the causes of their growth deficits are often unclear. We postulated that mutations in the gene for the insulin-like growth factor I receptor (IGF-IR) might underlie some cases of prenatal and postnatal growth failure. METHODS: We screened two groups of children for abnormalities in the IGF-IR gene. In one group of 42 patients with unexplained intrauterine growth retardation and subsequent short stature, we used single-strand conformation polymorphism analysis, followed by direct DNA sequencing of any abnormalities found. A second cohort consisted of 50 children with short stature who had elevated circulating IGF-I concentrations. Complete sequencing of the IGF-IR gene was performed with DNA from nine children. We also studied a control group of 43 children with normal birth weights. RESULTS: In the first cohort, we identified one girl who was a compound heterozygote for point mutations in exon 2 of the IGF-IR gene that altered the amino acid sequence to Arg108Gln in one allele and Lys115Asn in the other. Fibroblasts cultured from the patient had decreased IGF-I-receptor function, as compared with that in control fibroblasts. No such mutations were found in the 43 controls. In the second group, we identified one boy with a nonsense mutation (Arg59stop) that reduced the number of IGF-I receptors on fibroblasts. Both children had intrauterine growth retardation and poor postnatal growth. CONCLUSIONS: Mutations in the IGF-IR gene that lead to abnormalities in the function or number of IGF-I receptors may also retard intrauterine and subsequent growth in humans.

Amino Acid Sequence↗
PubMed2003

Multiple mutations of MYO1A, a cochlear-expressed gene, in sensorineural hearing loss.

Myosin I isozymes have been implicated in various motile processes, including organelle translocation, ion-channel gating, and cytoskeleton reorganization. Unconventional myosins were among the first family of proteins found to be associated with hearing loss in both humans and mice. Here, we report the identification of a nonsense mutation, of a trinucleotide insertion leading to an addition of an amino acid, and of six missense mutations in MYO1A cDNA sequence in a group of hearing-impaired patients from Italy. MYO1A, which is located within the DFNA48 locus, is the first myosin I family member found to be involved in causing deafness and may be a major contributor to autosomal dominant-hearing loss.

Amino Acid Substitution↗
PubMed2002

Mutations of p53 tumor suppressor gene in spontaneous canine mammary tumors.

Mutation of the p53 tumor suppressor gene has been related in the pathogenesis of numerous human and canine cancers, including breast cancers and mammary tumors. We have investigated exons 5-8 of the p53 gene for mutations in 20 spontaneous canine mammary tumors using polymerase chain reaction (PCR) with direct sequence analysis to evaluate the role of this gene in canine mammary tumorigenesis and analyzed to compare with other clinicopathological parameters including age, histology, stage, recurrence and death from tumor. Four missense (one case had two missense mutations) and one nonsense mutations were detected in 10 malignant lesions (40%), and two missense and one silent mutations were found in 10 benign mammary tumors (30%). Five of the missense mutations were located in highly conserved domains II, III, IV and V. After a follow-up period, four dogs showed a progression and three of these patients revealed death from mammary carcinoma with p53 mutation. These results demonstrated that the p53 gene mutations might be involved in the development of canine mammary tumors and contribute to the prognostic status in canine mammary carcinomas.

Animals↗