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PubMed1995

Mutational analysis of patients with X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked neurodegenerative disorder characterized by elevated very long chain fatty acid (VLCFA) levels, reduced activity of peroxisomal VLCFA-CoA ligase, and variable phenotypic expression. A putative gene for ALD was recently identified and surprisingly encodes a protein (ALDP) that belongs to a family of transmembrane transporters regulated or activated by ATP (the ABC proteins). We have examined genomic DNA from ALD probands for mutations in the putative ALD gene. We detected large deletions of the carboxyl-terminal portion of the gene in 4 of 112 probands. Twenty-five of the ALD probands whose ALD genes appeared normal by Southern blot analysis were surveyed for mutations by Single Strand Conformation Polymorphism (SSCP) procedures and DNA sequence analysis. SSCP variants were detected in 22 probands and none in 60 X-chromosomes from normal individuals. Mutations were detected in all of the ALD probands. The mutations were distributed throughout the gene and did not correlate with phenotype. Approximately half were non-recurrent missense mutations of which 64% occurred in CpG dinucleotides. There was a cluster of frameshift mutations in a small region of exon 5, including an identical AG deletion in 7 unrelated probands. These data strongly support the supposition that mutations in the putative ALD gene result in ALD.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2005

ATP1A2 mutations in 11 families with familial hemiplegic migraine.

Familial hemiplegic migraine (FHM) is an autosomal dominant form of migraine with aura. The disease is caused by mutations of at least three genes among which two have been identified, CACNA1A and ATP1A2. Very few mutations have been identified so far in ATP1A2. We screened the coding sequence of ATP1A2 in 26 unrelated FHM probands in whom CACNA1A screening was negative. A total of eight different mutations were identified in 11 of the probands (41%), including six missense mutations, one small deletion leading to a frameshift, and one in frame deletion. All were novel mutations. Two mutations were recurrent, in three and two families, respectively. Genotyping of 94 relatives of these 11 probands identified 47 mutation carriers, among whom 36 were clinically affected. Sequencing of all 23 exons in an ethnically matched panel detected only one exonic coding polymorphism.

Amino Acid Sequence↗
PubMed2002

Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia.

Mutations in the gene encoding cartilage oligomeric matrix protein ( COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). More than 40 mutations have been identified; however, genotype-phenotype relationships are not well delineated. Further, mutations other than in-frame insertion/deletions and substitutions have not been found, and currently known mutations are clustered within relatively small regions. Here we report the identification of nine novel and three recurrent COMP mutations in PSACH and MED patients. These include two novel types of mutations; the first, a gross deletion spanning an exon-intron junction, causes an exon deletion. The second, a frameshift mutation that results in a truncation of the C-terminal domain, is the first known truncating mutation in the COMP gene. The remaining mutations, other than a novel exon 18 mutation, affected highly conserved aspartate or cysteine residues in the calmodulin-like repeat (CLR) region. Genotype-phenotype analysis revealed a correlation between the position and type of mutations and the severity of short stature. Mutations in the seventh CLR produced more severe short stature compared with mutations elsewhere in the CLRs ( P=0.0003) and elsewhere in the COMP gene ( P=0.0007). Patients carrying mutations within the five-aspartates repeat (aa 469-473) in the seventh CLR were extremely short (below -6 SD). Patients with deletion mutations were significantly shorter than those with substitution mutations ( P=0.0024). These findings expand the mutation spectrum of the COMP gene and highlight genotype-phenotype relationships, facilitating improved genetic diagnosis and analysis of COMP function in humans.

Achondroplasia↗
PubMed2002

Dominant negative ATM mutations in breast cancer families.

BACKGROUND: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. METHODS: Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. RESULTS: In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. CONCLUSION: At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

Sequence diversity of the mucABD locus in Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

The mucA gene of the muc operon, which is instrumental in the control of the biosynthesis of the exopolysaccharide alginate, is a hotspot of mutation in Pseudomonas aeruginosa, a micro-organism that chronically colonizes the airways of individuals with cystic fibrosis (CF). The mucA, mucB and mucD genes were sequenced in nine environmental isolates from aquatic habitats, and in 37 P. aeruginosa strains isolated from 10 patients with CF, at onset or at a late stage of chronic airway colonization, in order to elucidate whether there was any association between mutation and background genotype. The 61 identified single nucleotide polymorphisms (SNPs) segregated into 18 mucABD genotypes. Acquired and de novo stop mucA mutations were present in 14 isolates (38 %) of five mucABD genotypes. DeltaG430 was the most frequent and recurrent mucA mutation detected in four genotypes. The classification of strains by mucABD genotype was generally concordant with that by genome-wide SpeI fragment pattern or multilocus SNP genotypes. The exceptions point to intragenic mosaicism and interclonal recombination as major forces for intraclonal evolution at the mucABD locus.

Adolescent↗
PubMed2003

Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin.

BACKGROUND: Posttransplant recurrence of focal segmental glomerulosclerosis (FSGS) occurs in a relevant proportion of FSGS patients and represents an important clinical emergency. It is taken as a proof of the existence of circulating permeability plasma factor(s) that are also putative effectors of original proteinuria in these patients. Familial forms of FSGS do not recur, but the discovery of numerous patients with sporadic FSGS and mutations of podocin (NPHS2, that is actually an inherited disease) who received a renal graft require a re-evaluation of the problem. METHODS: To evaluate the incidence of posttransplant recurrence of FSGS in patients with NPHS2, the authors screened for podocin mutations in 53 patients with the clinical and pathologic stigmata of FSGS who had renal failure and who had undergone renal transplantation.Results. Twelve children were found to carry a homozygous (n9) or a heterozygous (n4) mutation of podocin and were classified, according to current criteria, as patients with inherited FSGS. In 5 patients of this group (38%), proteinuria recurred after renal graft and in 2, renal biopsy results showed recurrence of FSGS. Prerecurrence serum of 3 patients of this cohort was tested for antipodocin antibodies with indirect immuno-Western utilizing human podocyte extracts and were found negative. The rate of FSGS recurrence was comparable in non-NPHS2-FSGS children (12 of 27) and adults (3 of 13). Also clinical outcome of recurrence and response to plasmapheresis and immunosuppressors were comparable, suggesting a common mechanism. CONCLUSION: These data show a high rate of FSGS recurrence in patients with NPHS2 mutations that is comparable with idiopathic FSGS and describe the successful therapeutic approach. Recurrence of an apparently inherited disease should stimulate a critical review of the mechanisms of recurrence and of original proteinuria in these cases.

Adolescent↗
PubMed1999

Amplification of the androgen receptor gene is associated with P53 mutation in hormone-refractory recurrent prostate cancer.

p53 protein expression of 30 hormone-refractory locally recurrent prostate cancers was compared with their matched untreated primary tumour specimens. In addition, androgen receptor (AR) gene amplification and p53 protein immunostaining were compared. p53 positivity increased during hormonal therapy from 17 per cent of the untreated primary tumours to 40 per cent of the hormone-refractory recurrences (p = 0.078). None of the p53-positive primary tumour specimens lost p53 positivity during hormonal therapy. Hormone-refractory recurrences with AR gene amplification more frequently (p = 0.0342) showed positive p53 immunostaining than tumours without AR gene amplification, 75 and 27 per cent, respectively. In summary, this study has shown that a cell clone with P53 mutation seems to be selected for during endocrine therapy and that positive p53 immunostaining correlates with AR gene amplification. These results suggest that inactivation of P53 may lead to genetic instability in a subset of prostate carcinomas enabling them to achieve properties, such as AR gene amplification, that allow them to grow in low levels of androgens and therefore cause tumour progression.

Aged↗
PubMed1990

Genetic analysis of a vital mammalian housekeeping locus using CHO cells that express a transfected mutant allele.

We describe a novel approach for the isolation of null mutations in a vital Chinese hamster ovary (CHO) cell housekeeping gene. Our experimental strategy required introduction of an expressible DNA clone encoding a recessive emetine-resistance allele of ribosomal protein S14 into wild-type CHO cells. Transgene heterozygote (TGH) cell lines, which harbor multiple emetine-resistance S14 transgenes, survive mutations that inactivate the CHO RPS14 locus by virtue of the transgenes' biological function. Null mutations in RPS14 yield TGH clones that display the transgene's drug-resistance phenotype. A large collection of emetine-resistant clones was isolated from one TGH cell line and shown to consist of three types of S14 mutations: (1) nonsense null mutations in the RPS14 protein coding sequence; (2) missense null mutations that affect S14 amino acid residues that have been conserved stringently during eukaryotic evolution; and (3) a recurrent missense mutation that results in a new, functional RPS14 emetine-resistance allele.

Amino Acid Sequence↗
PubMed1997

Deleterious mutations, variable epistatic interactions, and the evolution of recombination.

In this paper, we examine the conditions that allow increased recombination to evolve in the presence of recurrent deleterious mutation. We focus on a three-locus model first studied by Feldman et al. (1980), which follows the dynamics of a modifier locus that alters the recombination rate between two loci subject to deleterious mutation. Although Feldman et al. (1980) indicated that increased recombination might be favored if there is diminishing-returns epistasis, we show that alleles that increase the recombination rate can only invade if there is synergistic epistasis between the loci under selection. Even with synergistic epistasis, evolution at the modifier locus will lead to decreased recombination if the modifier locus is loosely linked and epistasis is strong. Using the multi-locus analysis of Barton (1995), we show that variability among loci in the sign and strength of epistasis further decreases the parameter space over which increased recombination may evolve. We conclude that, even with negative epistasis, increased recombination may only be favored when linkage is tight, especially if, as seems likely, epistatic interactions are highly variable among loci.

Animals↗
PubMed2004

[Haplotype of the BRCA2 6857delAA mutation in 4 families with breast/ovarian cancer].

BACKGROUND AND OBJECTIVE: It is estimated that 5-10% of all breast cancers are hereditary, mainly are due to germline mutations in the BRCA1 and BRCA2 genes. PATIENTS AND METHOD: A BRCA2 screening was carried out in familial breast/ovarian cancer at two centres in Spain and Chile. The 6857delAA mutation was identified in 3 Spanish families and one Chilean, all of them with Spanish ancestors. The BRCA2 haplotype of the 6857delAA carriers was analyzed using five microsatellite markers flanking the BRCA2 gene, spanning a region of 6 cM: cen-D13S260, D13S1698, (BRCA2), D13S171, D13S310 and D13S267-tel. RESULTS: Two families shared the allelic variants of the 5 microsatellites studied. Markers D13S260 and D13S267 differed in one allele in two families, respectively. The defined haplotype was absent in non-carriers from these families, and was not detected in 100 control chromosomes without the mutation. CONCLUSIONS: Our results suggest the existence of a common ancestry with the mutation originating in the Northeast of Spain. Given the migratory movements from Spain to Latin America, the screening of recurrent Spanish mutations can be useful in establishing a more rational and cost-effective analysis in such populations.

Breast Neoplasms↗
PubMed2003

Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD/PKHD1).

Autosomal recessive polycystic kidney disease (ARPKD/PKHD1) is an important cause of renal-related and liver-related morbidity and mortality in childhood. Recently mutations in the PKHD1 gene on chromosome 6p21.1-p12 have been identified as the molecular cause of ARPKD. The longest continuous open reading frame (ORF) is encoded by a 67-exon transcript and predicted to yield a 4074-amino acid protein ("polyductin") of thus far unknown function. By now, a total of 29 different PKHD1 mutations have been described. This study reports mutation screening in 90 ARPKD patients and identifies mutations in 110 alleles making up a detection rate of 61%. Thirty-four of the detected mutations have not been reported previously. Two underlying mutations in 40 patients and one mutation in 30 cases are disclosed, and no mutation was detected on the remaining chromosomes. Mutations were found to be scattered throughout the gene without evidence of clustering at specific sites. About 45% of the changes were predicted to truncate the protein. All missense mutations were nonconservative, with the affected amino acid residues found to be conserved in the murine polyductin orthologue. One recurrent missense mutation (T36M) likely represents a mutational hotspot and occurs in a variety of populations. Two founder mutations (R496X and V3471G) make up about 60% of PKHD1 mutations in the Finnish population. Preliminary genotype-phenotype correlations could be established for the type of mutation rather than for the site of the individual mutation. All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise. PKHD1 mutation analysis is a powerful tool to establish the molecular cause of ARPKD in a given family. Direct identification of mutations allows an unequivocal diagnosis and accurate genetic counseling even in families displaying diagnostic challenges.

Adolescent↗
PubMed2000

The fitness effects of spontaneous mutations in Caenorhabditis elegans.

Spontaneous mutation to mildly deleterious alleles has emerged as a potentially unifying component of a variety of observations in evolutionary genetics and molecular evolution. However, the biological significance of hypotheses based on mildly deleterious mutation depends critically on the rate at which new mutations arise and on their average effects. A long-term mutation-accumulation experiment with replicate lines of the nematode Caenorhabditis elegans maintained by single-progeny descent indicates that recurrent spontaneous mutation causes approximately 0.1% decline in fitness per generation, which is about an order of magnitude less than that suggested by previous studies with Drosophila. Two rather different approaches, Bateman-Mukai and maximum likelihood, suggest that this observation, along with the observed rate of increase in the variance of fitness among lines, is consistent with a genomic deleterious mutation rate for fitness of approximately 0.03 per generation and with an average homozygous effect of approximately 12%. The distribution of mutational effects for fitness appears to have a relatively low coefficient of variation, being no more extreme than expected for a negative exponential, and for one composite fitness measure (total progeny production) approaches constancy of effects. These results are derived from assays in a benign environment. At stressful temperatures, estimates of the genomic deleterious mutation rate (for genes expressed at such temperatures) is sixfold lower, whereas those for the average homozygous effect is approximately eightfold higher. Our results are reasonably compatible with existing estimates for flies, when one considers the differences between these species in the number of germ-line cell divisions per generation and the magnitude of transposable element activity.

Animals↗
PubMed1996

Mucopolysaccharidosis type II (Hunter syndrome): mutation "hot spots" in the iduronate-2-sulfatase gene.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-chromosomal storage disorder due to deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). We have identified IDS mutations in a total of 31 families/patients with MPS II, of which 20 are novel and unique and a further 1 is novel but has been found in 3 unrelated patients. One of the mutations detected is of special interest as an AG-->G substitution in an intron, far apart from the coding region, is deleterious by creating a new 5'-splice-donor site that results in the inclusion of a 78-bp intronic sequence. While the distribution of gene rearrangements (deletions, insertions, and duplications) of <20 bp seems to be random over the IDS gene, the analysis of a total of 101 point mutations lying within the coding region shows that they tend to be more frequent in exons III, VIII, and IX. Forty-seven percent of the point mutations are at CpG dinucleotides, of which G:C-to-A:T transitions constitute nearly 80%. Almost all recurrent point mutations involve CpG sites. Analysis of a collective of 50 families studied in our laboratory, to date, revealed that mutations occur more frequently in male meioses (estimated male-to-female ratio between 3.76 and 6.3).

Alternative Splicing↗
PubMed1997

The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon.

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mutations, which are spread throughout the gene, are presented. This brings the total reported to date to 35, which represents a detection rate of 60%. Of the mutations that have been reported to date, all but one result in the introduction of a premature-termination codon into the predicted protein, treacle. Moreover, the mutations are largely family specific, although a common 5 bp deletion in exon 24 (seven different families) and a recurrent splicing mutation in intron 3 (two different families) have been identified. This mutational spectrum supports the hypothesis that TCS results from haploinsufficiency.

Chromosomes, Human, Pair 5↗
PubMed1998

Hereditary protein C deficiency with recurrent thrombosis: identification of a missense mutation (C6218T).

Protein C is the central component of a major anti-thrombotic regulatory system and individuals with hereditary protein C deficiency (PCD) tend to have an increased risk of thromboembolism. During the last several years, mutations causing PCD have been identified in Western countries and in Japanese. In the present study, we report a case of hereditary PCD with a missense mutation (C6218T) in a 44 year old female with recurrent pulmonary thromboembolism. The protein C activity (35%) and antigen (58%) levels in this patient were decreased. Furthermore, we have identified the same molecular defect and PCD in other asymptomatic family members including proband's mother and two daughters and one son. To our knowledge, this is the first case of hereditary PCD with identified genetic defect in the Korean population, which may be one of hot spots for mutation in the protein C gene.

Adult↗
PubMed2007

Combined thrombophilic mutations in women with unexplained recurrent miscarriage.

PROBLEM: To compare the prevalence of five common thrombophilic polymorphisms and their combination in women with recurrent miscarriage and a control group. METHOD OF STUDY: Genomic analysis using polymerase chain reaction (PCR) was carried out in patients with two or more miscarriages and controls for Factor V Leiden, Factor V A1299H (HR2), Factor II G20210A, MTHFR C677T and MTHFR A1298C. Secondary analyses were made for number of miscarriages and gestational age at miscarriage. RESULTS: None the mutations was associated with significantly increased risk for recurrent miscarriage. The prevalence of combined thrombophilias (4/88 versus 2/88) did not increase the risk for miscarriage (OR 2.04, 95% CI 0.36-11.47). Although virtually all patients with thrombophilia had miscarriages 10 weeks' subgroup. There was no difference in the distribution of Factor V Leiden (P=1.000), FII G20210A (P=0.652), and MTHFR C677T (P=0.869) between patients with two and three or more miscarriages, whereas MTHFR A1298C was more common among patients with two miscarriages (P=0.017). CONCLUSIONS: Combinations of the five thrombophilic mutations studied are an uncommon event with heterogeneous pattern and they do not significantly increase the risk for miscarriage.

Abortion, Habitual↗
PubMed2001

XV-2c/KM-19 haplotype analysis of cystic fibrosis mutations in Mexican patients.

We analyzed 97 unrelated Mexican cystic fibrosis (CF) patients and their first-degree relatives to study the association of XV2C/TaqI/KM19/PstI haplotypes with CF mutations in this population. Haplotype phases could be established in 148 CF and 110 normal chromosomes, and haplotype distributions of normal and CF chromosomes differed significantly (P < 0.001). DeltaF508 and G542X mutations accounted for 56% of CF chromosomes and were found to be associated with haplotype B in 97.2% and 72.7% of chromosomes, respectively. The haplotype distribution of CF chromosomes carrying other rare and unknown mutations was similar to that of normal chromosomes (P > 0.05), haplotypes A and C being the most frequent. This is in accordance with the extensive heterogeneity and the spectrum of mutations reported in Mexican CF patients. We also report the haplotype distribution of all informative chromosomes bearing rare mutations; some were found to be associated with previously reported haplotypes, whereas others were found on different haplotypes. Recombination or recurrence of mutations may explain these different associations, although other intragenic markers must be used to better understand the origin and dispersion of CF mutations in our country. XK haplotype analysis allowed carrier detection among sibs in 24.3% of families, showing that this method may be useful for carrier detection in populations with high allelic heterogeneity.

Cystic Fibrosis↗
PubMed2005

Progressive familial intrahepatic cholestasis: genetic disorders of biliary transporters.

Progressive familial intrahepatic cholestasis types 1, 2 and 3 are childhood diseases of the liver. Benign recurrent intrahepatic cholestasis is predominantly an adult form with similar clinical symptoms that spontaneously resolve. These genetic disorders have significantly helped to unravel the basic mechanisms of the canalicular bile transport processes. Progressive familial intrahepatic cholestasis type 1 involves a gene also linked to benign recurrent intrahepatic cholestasis. The gene codes for an aminophospholipid translocase protein that maintains the integrity of the membrane. How a mutation in this protein causes cholestasis is unknown but is thought to involve the enterohepatic recirculation of bile acids. Progressive familial intrahepatic cholestasis types 2 and 3 involve the canalicular bile salt export pump and a phospholipid translocase, respectively, both of which are fundamental to bile secretion. This review covers the clinical manifestations, genetics, treatment and mechanism of each disease.

ATP-Binding Cassette Transporters↗