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PubMed1991

Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism.

In addition to its classical effects on growth, growth hormone (GH) has been shown to have a number of other actions, all of which are initiated by an interaction with specific high affinity receptors present in a variety of tissues. Purification of a rabbit liver protein via its ability to bind GH has allowed the isolation of a cDNA encoding a putative human growth hormone receptor that belongs to a new class of transmembrane receptors. We have previously shown that this putative growth hormone receptor gene is genetically linked to Laron dwarfism, a rare autosomal recessive syndrome caused by target resistance to GH. Nevertheless, the inability to express the corresponding full-length coding sequence and the lack of a test for growth-promoting function have hampered a direct confirmation of its role in growth. We have now identified three nonsense mutations within this growth hormone receptor gene, lying at positions corresponding to the amino terminal extremity and causing a truncation of the molecule, thereby deleting a large portion of both the GH binding domain and the full transmembrane and intracellular domains. Three independent patients with Laron dwarfism born of consanguineous parents were homozygous for these defects. Two defects were identical and consisted of a CG to TG transition. Not only do these results confirm the growth-promoting activity of this receptor but they also suggest that CpG doublets may represent hot spots for mutations in the growth hormone receptor gene that are responsible for hereditary dwarfism.

Dwarfism↗

PubMed1998

A recurrent missense mutation in the KAL gene in patients with X-linked Kallmann's syndrome.

Kallmann's syndrome (KS) is defined by the association of hypogonadotropic hypogonadism and anosmia or hyposmia. Segregation analysis in familial cases has demonstrated diverse inheritance patterns, suggesting the existence of several genes regulating GnRH secretion. Genetic defects have been demonstrated in the KAL gene, located on the Xp22.3 region, explaining the X-linked form of the disease. We report molecular findings regarding the KAL gene in 12 unrelated males with X-linked KS. PCR of the 14 exons of the KAL gene was performed on genomic DNA. PCR products of all exons were purified and sequenced. Genetic defects in the KAL gene were found in 7 patients. One exhibits a deletion from exon 3 to exon 5. Six individuals present a previously unidentified missense mutation in exon 11, consisting of a G to A substitution at codon 514 (GAA to AAA). In the remaining 5 individuals, no mutations were observed. We also found three different polymorphic changes. The first one, in exon 2, had not been reported previously. The other two were located at exons 11 and 12. The deletion described, comprises only part (exon 5) of the coding region of the first fibronectin type III-like repeat of the KAL protein. The rest of the deletion comprises part of the conserved cysteine-rich N-terminal region that corresponds to the whey acidic protein motif. The same missense mutation was found in 6 of the 12 patients, indicating the possibility that it derived from a common ancestor or suggesting the presence of a hot spot in this region of the gene.

Adolescent↗

PubMed1994

The spectrum of beta-thalassemia mutations in the Oran region of Algeria.

In order to delineate the spectrum of beta-globin gene defects causing beta-thalassemia in the Oran region of Algeria, we have analyzed a representative sample of 31 beta-thalassemia patients. This led to the detection of 10 mutations. Four of them [nonsense codon 39 (C->T), IVS-I-110 (G->A), IVS-I-2 (T->C), and frameshift codon 6 (-A)] account for approximately 77% of the beta-thalassemia chromosomes. Three of these mutants are also widespread in Mediterranean populations, whereas the fourth, IVS-I-2 (T->C), appears typical of the Oranese population. The six other variants are less frequent. The possible origin of these mutated alleles, either by recurrent mutational event or by migration from other populations, is discussed.

Adult↗

PubMedDate not supplied

[Sarcoglycanopathies].

INTRODUCTION: Identification of several clinical pictures in relation to a deficit of various protein components of the sarcoglycan complex, has allowed a new classification to be established for muscular dystrophies, correlating the protein alpha, beta, gamma, sigma deficit with a type of girdle dystrophy ('Limb-Girdle Muscular Dystrophy', LGMD) and the genomic identification respectively: 2D/17, 2E/4q12, 2C/13q12, 2E/4q12, 2F/5q33. The correlation between the various proteins and complexes and the dystrophin is known as Dystrophin Associated Glycoproteins (DAG) and Dystrophin Related Proteins (DRP). This interrelationship is fundamental to the study of the different components and the key to immunohistochemical study and evaluation amongst other things. Patients with alpha-sarcoglycan deficiency (LGMD 2D) show great clinical and genetic heterogeneity sometimes leading to severe degrees of muscular dystrophy similar to Duchenne muscular dystrophy. The mutation R77C is a recurrent mutation and the cause in over one third of the patients with this deficiency. Absence of gamma-sarcoglycan is also a cause of severe muscular dystrophies with the Duchenne phenotype. It has been described in the Mediterranean region, Japan and Brazil. The delta 525T mutation is the commonest and also, as occurs with C283Y (specific to the gypsy race), is a foundational mutation. Deficit of beta-sarcoglycan (LGMD 2E) gives rise to different grades of clinical severity, frequently with cardiac involvement. At present the phenotype of sigma-sarcoglycan deficit (LGMD 2F) has yet to be described [REV NEUROL 1999; 28: 150-3].

Adult↗

PubMed1989

Recurrent somatic mutations in mouse antibodies to p-azophenylarsonate increase affinity for hapten.

Two mouse mAb specific for the hapten p-azophenylarsonate and encoded by the same combination of germ-line V, D, and J genes differ 200-fold in affinity for hapten. We determined the amino acid sequences of the V regions of the high affinity antibody and compared them to the published sequences of the low affinity antibody which is not somatically mutated. Of 19 amino acid substitutions, two, Ile57 and Thr58 in the H chain, also occur, either alone or together, in other somatically mutated antibodies specific for p-azophenylarsonate; these antibodies have been independently isolated. Introduction of either one of these mutations alone into the low affinity antibody by oligonucleotide-directed mutagenesis increased the antibody affinity for hapten three- to fourfold, whereas introduction of both mutations together conferred an eightfold increase in affinity. These results support the hypothesis that somatic mutations are selected on the basis of the affinity for antigen that they confer, and suggest that even relatively small increases in affinity may be selected, probably in a sequential manner.

Amino Acid Sequence↗

PubMed1995

p53 wild-type and p53 nullizygous Big Blue transgenic mice have similar frequencies and patterns of observed mutation in liver, spleen and brain.

Transgenic mouse mutation detection systems offer a powerful tool for analysis of spontaneous and induced mutations in vivo. Mice doubly transgenic for a null mutation of the p53 tumor suppressor gene and a lambda shuttle vector harboring the lacI gene were utilized to examine the rate and pattern of spontaneous somatic mutation of the lacI transgene in vivo. Three somatic tissues were examined: liver, spleen and brain. At 6 weeks of age, three p53 wild type (+/+) and three p53 nullizygous (-/-), lacI (+/-) male mice were analysed. The mutation frequencies in the two genotypes were similar. The mutant frequencies for wild type (+/+) and nullizygous (-/-) p53 genotypes were, respectively, 4.2 x 10(-5) and 3.6 x 10(-5) in the liver, 4.3 x 10(-5) and 3.4 x 10(-5) in the spleen and 2.8 x 10(-5-) and 3.0 x 10(-5) in the brain. When the data from the three tissues were combined, the mutant frequency was 3.7 x 10(-5) for the (+/+) genotype and 3.3 x 10(-5) for the (-/-) genotype. By sequencing both strands in the DNA-binding region of the lacI gene, 91 mutations were found. When recurrent mutations in the same mouse were excluded, a total of 67 definitely independent mutations were found. No statistically significant differences were found in the mutational spectra between the two genotypes when the three tissues were analysed individually or combined (P = 0.58). These findings suggest a need to reconsider the general form of hypothesis that the p53 gene serves as the 'guardian of the genome'.

Animals↗

PubMed1995

Achondroplasia is defined by recurrent G380R mutations of FGFR3.

Genomic DNA from 154 unrelated individuals with achondroplasia was evaluated for mutations in the fibroblast growth factor receptor 3 (FGFR3) transmembrane domain. All but one, an atypical case, were found to have a glycine-to-arginine substitution at codon 380. Of these, 150 had a G-to-A transition at nt 1138, and 3 had a G-to-C transversion at this same position. On the basis of estimates of the prevalence of achondroplasia, the mutation rate at the FGFR3 1138 guanosine nucleotide is two to three orders of magnitude higher than that previously reported for tranversions and transitions in CpG dinucleotides. To date, this represents the most mutable single nucleotide reported in the human genome. The homogeneity of mutations in achondroplasia is unprecedented for an autosomal dominant disorder and may explain the relative lack of heterogeneity in the achondroplasia phenotype.

Achondroplasia↗

PubMed1994

Recurrent nonsense mutations within the type VII collagen gene in patients with severe recessive dystrophic epidermolysis bullosa.

The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopeau-Siemens type; HS-RDEB) is a life-threatening disease characterized by extreme mucocutaneous fragility associated with absent or markedly altered anchoring fibrils (AF). Recently, we reported linkage between HS-RDEB and the type VII collagen gene (COL7A1), which encodes the major component of AF. In this study, we investigated 52 unrelated HS-RDEB patients and 2 patients with RDEB inversa for the presence, at CpG dinucleotides, of mutations changing CGA arginine codons to premature stop codons TGA within the COL7A1 gene. Eight exons containing 10 CGA codons located in the amino-terminal domain of the COL7A1 gene were studied. Mutation analysis was performed using denaturing gradient gel electrophoresis of PCR-amplified genomic fragments. Direct sequencing of PCR-amplified products with altered electrophoretic mobility led to the characterization of three premature stop codons, each in a single COL7A1 allele, in four patients. Two patients (one affected with HS-RDEB and the other with RDEB inversa) have the same C-to-T transition at arginine codon 109. Two other HS-RDEB patients have a C-to-T transition at arginine 1213 and 1216, respectively. These nonsense mutations predict the truncation of approximately 56%-92% of the polypeptide, including the collagenous and the noncollagenous NC-2 domains. On the basis of linkage analysis, which showed no evidence for locus heterogeneity in RDEB, it is expected that these patients are compound heterozygotes and have additional mutations on the other COL7A1 allele, leading to impaired AF formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1998

Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome.

Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectodermal involvement, demonstrates phenotypic overlap in some patients with Noonan syndrome (NS), ultimately resulting in the so-called neurofibromatosis-Noonan syndrome (NF-NS). A strong association of the two phenotypic traits was recently illustrated by a four-generation family, although NF1 and NS were eventually demonstrated to segregate independently on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J Med Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial association. Using the protein truncation assay, a nonsense mutation (C2446T-->R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specifying region of the gene. R816X creates a recognition site for endonuclease HphI, absent in 2 individuals with NS only. Screening 184 unrelated NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of genotype-phenotype correlation in these individuals, clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.

DNA Mutational Analysis↗

PubMed2000

Genotype-phenotype relationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations.

BACKGROUND: Two genes have been implicated in the development of cutaneous malignant melanoma (CMM). CDK4 (the gene encoding cyclin-dependent kinase 4, an oncogene) has exhibited germline mutations found in only three melanoma-prone families to date. CDKN2A is a tumor suppressor gene that encodes p16 (which inhibits activity of the cyclin D1-CDK4 complex) with germline mutations detected in 10%-25% of melanoma-prone families, some of whom are also prone to pancreatic cancer. METHODS: We compared 104 CMM patients from 17 CDKN2A families and 12 CMM case subjects from two CDK4 families. We used nonparametric statistics to test for differences in median age at first CMM diagnosis, numbers of CMMs, and numbers of nevi. The three recurrent mutations were haplotyped. All P values were two-sided. RESULTS: The median age at CMM diagnosis (P =.70) and the median numbers of CMMs (P =.73) did not differ between CMM case subjects from CDKN2A versus CDK4 families. Assessment of CMM case subjects from CDKN2A families with and without pancreatic cancer revealed no statistically significant differences in median age at diagnosis (P =.80) or in tumor number (P =.24). There was, however, a statistically significant difference in age-adjusted median numbers of nevi (P =.004), and CMM case subjects from CDKN2A families without pancreatic cancer had greater numbers of nevi. Recurrent CDKN2A mutations were a change from valine to aspartic acid at codon 126 (n = 3) and from glycine to tryptophan at codon 101 (n = 3). Six CDKN2A families had pancreatic cancer. Both CDK4 families carried a mutation resulting in an arginine-to-cysteine substitution at codon 24. Analyses of recurrent CDKN2A and CDK4 mutations suggested common haplotypes. CONCLUSIONS: The recurrent CDKN2A mutations were observed in families with and without pancreatic cancer, which suggests that other factors may be involved in the development of pancreatic cancer. Despite hypothetical differences in the mechanisms of action between CDKN2A and CDK4, clinical factors were indistinguishable between CMM case subjects from CDKN2A versus CDK4 families.

Adolescent↗

PubMed1998

Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Mutations in brief no. 205. Online.

Mutations in the human P gene lead to oculocutaneous albinism type 2 (OCA2, MIM #203200), the most common type of albinism in humans. The P gene encodes a 110 kDa protein that is associated with melonosomal membranes and contains 12 potential membrane spanning domains. The specific function of the P protein is currently unknown. We report 7 new mutations in the P gene associated with OCA2. This includes 6 missense mutations (S86R, C112F, A368V, T592I, A724P and A787V) and one frameshift mutation (1047del7). We also report 8 polymorphisms including one amino acid substitution, D/A257. We and others have found many polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, making molecular diagnosis problematic. In contrast to this is the tyrosinase gene associated with OCA1, with a limited number of polymorphic variations in the coding region. There is also no apparent clustering of P gene missense mutations in contrast to the clustering observed by the tyrosinase gene missense mutations that define functional domains of the protein. Further mutational analysis is needed to help define the critical functional domains of the P protein and to allow a definitive diagnosis of OCA2.

Albinism, Oculocutaneous↗

PubMed2026

Tumor Mutational Concordance and Recurrence Timing in Hepatocellular Carcinoma.

INTRODUCTION: In hepatocellular carcinoma (HCC), intrahepatic recurrence includes true recurrence from clonal relapse and multicentric recurrence from de novo tumorigenesis. Recurrence timing is used to distinguish these types; however, its accuracy remains unclear. This study aimed to classify recurrent tumors based on somatic mutational concordance and assess the validity of recurrence timing. METHODS: Whole-exome sequencing was performed on paired primary and recurrent HCC tumors from 49 patients enrolled in a prospective institutional omics project. Tumors with ≥ 10 shared somatic mutations were classified as true recurrence. Clinicopathological features, recurrence timing, driver mutation patterns, and survival outcomes were compared between recurrence types. Mutational concordance was quantified using shared variant counts and the Jaccard similarity index. RESULTS: Of the 49 patients, 22 (44.9%) showed true recurrence and 27 (55.1%) had multicentric recurrence. Multicentric recurrence tumors harbored no shared variants or only a single shared variant with the primary tumor. True recurrence was associated with significantly higher concordance in histological differentiation and Edmondson-Steiner grading and greater retention of CTNNB1, TP53, ARID1A, and KEAP1 mutations. The number of shared variants (median: 115 vs. 0, and p < 0.001) and the Jaccard index (median: 0.44 vs. 0.00 and p < 0.001) were significantly higher in the true recurrence group. Recurrence timing was inconsistently correlated with mutational concordance, although a 3-year cutoff yielded significant separation. CONCLUSION: Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.

clonal relapse↗

PubMed1998

Novel COL7A1 mutations in dystrophic forms of epidermolysis bullosa.

Mutations in the type VII collagen gene (COL7A1) have been shown to underlie different variants of dystrophic epidermolysis bullosa (DEB). Examination of the genetic database indicates that most of the mutations are family specific, with few recurrent mutations. To facilitate further refinement of genotype/phenotype correlations in DEB, we have examined a cohort of nine families with DEB (seven recessively and two dominantly inherited) by a mutation detection strategy based on polymerase chain reaction amplification of COL7A1 genomic sequences, followed by heteroduplex scanning and direct nucleotide sequencing. The results revealed 16 allelic mutations, 11 of them being novel, previously unpublished. The genetic information was also used for prenatal testing in a family at risk for recurrence of a severe, Hallopeau-Siemens type of RDEB. These data contribute to the expanding database of COL7A1 mutations in DEB.

Adult↗

PubMed2025

Estimation of demography and mutation rates from one million haploid genomes.

As genetic sequencing costs have plummeted, datasets with sizes previously unthinkable have begun to appear. Such datasets present opportunities to learn about evolutionary history, particularly via rare alleles that record the very recent past. However, beyond the computational challenges inherent in the analysis of many large-scale datasets, large population-genetic datasets present theoretical problems. In particular, the majority of population-genetic tools require the assumption that each mutant allele in the sample is the result of a single mutation (the "infinite-sites" assumption), which is violated in large samples. Here, we present DR EVIL, a method for estimating mutation rates and recent demographic history from very large samples. DR EVIL avoids the infinite-sites assumption by using a diffusion approximation to a branching-process model with recurrent mutation. This approach results in tractable likelihoods that are accurate for rare alleles. We show that DR EVIL performs well in simulations and apply it to rare-variant data from one million haploid samples. We identify mutation-rate heterogeneity even after accounting for trinucleotide context and methylation status. We also predict that at modern sample sizes, the alleles at most polymorphic sites with high mutation rates represent the descendants of multiple mutation events.

Haploidy↗

PubMed2000

OCRL1 mutation analysis in French Lowe syndrome patients: implications for molecular diagnosis strategy and genetic counseling.

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked recessively inherited disease characterized by a severe pleiotropic phenotype including mental retardation, bilateral congenital cataract, and renal Fanconi syndrome. The gene responsible for OCRL encodes an inositol polyphosphate-5-phosphatase. We performed mutation analysis in 36 families and characterized 27 new mutations with two of them being recurrent mutations. The panel of mutations consisted of 27 truncating mutations (frameshift, nonsense, splice site mutations, and large genomic deletions), one in-frame deletion, and six missense mutations. The four large genomic deletions occurred in the first half of the gene, whereas all the remaining mutations took place in the second part of the gene and were concentrated in a few exons. This distribution may be of interest in terms of screening strategy when looking for unknown mutations. Haplotyping of the families was performed to analyze segregation of the mutated loci, and revealed a somatic mosaicism in one family. This is the second case of mosaicism we characterized in a total panel of 44 unrelated families affected by Lowe's syndrome. Considering the low number of families investigated, it appeared that somatic and germinal mosaicisms are quite common in this disease and must be taken into account for genetic counseling.

Alternative Splicing↗

PubMed1998

The biochemical and molecular spectrum of ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTCase) deficiency, the most common inherited urea cycle disorder, is transmitted as an X-linked trait. The clinical phenotype in affected males as well as heterozygous females shows a spectrum of severity ranging from neonatal hyperammonaemic coma to asymptomatic adults. The ornithine transcarbamylase enzyme is a trimer with three active sites per holoenzyme molecule, each of which is composed of an interdomain region of one polypeptide and a polar domain of the adjacent polypeptide. The OTC gene is located on the short arm of the X-chromosome and one of the two alleles undergoes inactivation in female cells. Approximately 140 mutations have been found in families affected with OTCase deficiency, most having their own 'private' mutation. Large deletions of one exon or more are seen in approximately 7% of patients, small deletions or insertions are seen in about 9%, and the remaining mutations are single base substitutions. Approximately 15% of mutations affect RNA splicing sites. The recurrent mutations are distributed equally among CpG dinucleotide hot spots. Generally, mutations causing neonatal disease affect amino acid residues that are 'buried' in the interior of the enzyme, especially around the active site, while those associated with late onset and milder phenotypes tend to be located on the surface of the protein. Very few mutations have been found in the sequence of the leader peptide, proportionally much fewer than in the sequence of the mature enzyme. Only few of the mutations have been expressed in bacteria or mammalian cells for the study of their deleterious mechanisms. Examples of expressed mutations include R277W and R277Q associated with late-onset disease, which markedly increase the Km for ornithine, shift the pH optimum to more alkaline and decrease the thermal stability of the purified mutant enzyme. R141Q (neonatal disease) disrupts the active site, whereas the purified R40H mutant has normal catalytic function and this mutation is likely to affect posttranslational processing such as mitochondrial targeting. It appears that most new mutations occur in male sperm and are then passed on to a transmitting heterozygous female. Uncommonly, mild mutations are transmitted by asymptomatic males to their daughters, subsequently resulting in clinical disease of males in future generations. The causes for variable expressivity of these mutations are currently unknown but are likely to involve a combination of environmental and genetic modifiers.

Adult↗

PubMed2001

Molecular confirmation of the unique phenotype of epidermolysis bullosa simplex with mottled pigmentation.

BACKGROUND: A distinctive subtype of epidermolysis bullosa simplex, with the additional feature of mottled pigmentation (EBS-MP), was initially characterized in a Swedish family in 1979, and seven further families have been reported. Features of EBS-MP that are observed in most affected patients include acral blistering early in childhood, mottled pigmentation distributed in a number of sites, focal punctate hyperkeratoses of the palms and soles, and dystrophic, thickened nails. The genetic basis of EBS-MP has been ascribed in five unrelated families to a heterozygous point mutation, P25L, in the non-helical V1 domain of K5. OBJECTIVES: We report a clinical, ultrastructural and molecular study of two of the earliest families to be clinically characterized as EBS-MP. METHODS: The P25L mutation was identified in all affected members of each of these families, bringing the total number of EBS-MP families with this mutation to seven. RESULTS: This unusual recurrent mutation may uniquely cause EBS-MP. CONCLUSIONS: While the exact molecular mechanisms by which this mutation causes epidermolysis, palmoplantar keratoderma and pigmentation remain elusive, we suggest possible molecular mechanisms through which the P25L substitution could cause this unusual phenotype.

Adolescent↗

PubMed1997

A complex allele (1064delTC and IVS2 + 22ins7) in the peripherin/RDS gene in retinitis pigmentosa with macular dystrophy.

Because mutations in the peripherin/RDS gene have been found in retinal dystrophies involving the macula, we examined various types of macular dystrophies from southern France to characterize sequence variations that may be associated with these conditions. DNA sequence analysis of the full coding and flanking regions of the peripherin/RDS gene was performed in fifteen unrelated patients with different types of macular dystrophy, including nine with retinitis pigmentosa (RP). Of the 15 probands with macular disease, two (13.3%) were found to carry a mutation in the peripherin/RDS gene. The recurrent mutation P216S was identified in a pedigree with autosomal dominant RP. A previously unreported complex allele (1064delTC associated with IVS2 + 22ins7) that is predicted to result in the premature termination of peripherin/RDS synthesis was identified in a sporadic case of macular atrophy with RP. We also report eight novel neutral sequence variations in the peripherin/RDS gene, most of them found in the 3' untranslated part of the gene.

Adult↗