Molecular basis of HNPCC: Mutations of MMR genesPapadopoulos, Nickolas; Lindblom, Annika
doi: 10.1002/(sici)1098-1004(1997)10:2<89::aid-humu1>3.0.co;2-hpmid: 9259192
Hereditary nonpolyposis colorectal cancer (HNPCC) is inherited as a dominant disorder caused by germline defects in one of at least four mismatch repair (MMR) genes. Two of these genes, hMSH2 and hMLH1, account for the vast majority of the germline mutations in HNPCC kindreds, whereas hPMS1 and hPMS2 are mutated in only few families. MMR genes also are susceptible to somatic mutations in sporadic tumors. The mutational spectrum of the MMR genes shows no predominant type of mutation. Furthermore, the mutations are spread throughout the length of the genes, with no significant hot spots. Identification of MMR genes as the cause of HNPCC made presymptomatic diagnosis a reality. However, the presence of multiple genes and the heterogeneity of mutations present challenges to the development of diagnostic tests for this disease. Hum Mutat 10:89–99, 1997. © 1997 Wiley‐Liss, Inc.
Diversity of ATM gene mutations detected in patients with ataxia‐telangiectasiaConcannon, Patrick; Gatti, Richard A.
doi: 10.1002/(sici)1098-1004(1997)10:2<100::aid-humu2>3.0.co;2-opmid: 9259193
The ataxia‐telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia‐telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More than 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (>70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning ˜150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved. Hum Mutat 10:100–107, 1997. © 1997 Wiley‐Liss, Inc.
Rapid characterization of the variable length polythymidine tract in the cystic fibrosis (CFTR) gene: Association of the 5T allele with selected CFTR mutations and its incidence in atypical sinopulmonary diseaseFriedman, Kenneth J.; Heim, Ruth A.; Knowles, Michael R.; Silverman, Lawrence M.
doi: 10.1002/(sici)1098-1004(1997)10:2<108::aid-humu3>3.0.co;2-gpmid: 9259194
The CFTR intron 8 variable length polythymidine tract modulates the cystic fibrosis (CF) phenotype associated with the mutation R117H. To explore whether other mutations reside on multiple intron 8 backgrounds with discernible impacts on phenotype, we developed an allele‐specific PCR assay to characterize this locus. Our approach types samples rapidly without the use of radioisotopes. Polythymidine alleles were identified for mutations either associated with a wide range of clinical phenotypes (R117H, R347P, G85E, D1152H, R334W, 2789+5 G>A, 3849+10kb C>T), and/or located at hypermutable CpG loci (R117H, 3849+10kb C>T, R553X, R334W, S945L and R75Q). R117H was detected in cis with each of three alleles (5T, 7T, 9T) at the intron 8 locus. The novel R117H‐9T association was detected in a 10‐month old African‐American male with borderline‐to‐mildly elevated sweat chloride values (˜50–66 mEq/L). All other mutations studied were associated with 7T except 3849+10kb C>T, which was detected on both 7T and 9T backgrounds, but not 5T. Three individuals with a ΔF508/3849+10kb C>T genotype were 9T,9T and had pancreatic sufficiency and normal sweat chloride values, whereas 15 others who carried 3849+10kb C>T on a 7T background had variable pancreatic function (sufficient, n = 12, insufficient, n = 3), and variable sweat chloride values (normal, n = 12, elevated, n = 3). Surprisingly, when not associated with known CFTR mutations, 5T was detected with elevated frequency among individuals with sinopulmonary disease of ill‐defined etiology, but with some characteristics of variant CF. In summary, the 5T allele was not found in cis with CF‐causing mutations besides R117H, but an elevated 5T allele frequency in variant CF patients suggests 5T may be associated with disease in some situations. Hum Mutat 10:108–115, 1997. © 1997 Wiley‐Liss, Inc.
Spectrum of LDL receptor gene mutations in heterozygous familial hypercholesterolemiaDay, INM; Whittall, RA; O'Dell, SD; Haddad, L; Bolla, MK; Gudnason, V; Humphries, SE
doi: 10.1002/(sici)1098-1004(1997)10:2<116::aid-humu4>3.0.co;2-ipmid: 9259195
Familial hypercholesterolemia by usual definition reflects mutations of the LDL‐receptor gene. Extensive molecular characterization of mutations ascertained mainly through homozygotes (the Dallas collection) has been presented by Hobbs et al. (Hum Mutat 1:445–466, 1992). This paper catalogues a spectrum of 134 mutations (27 novel mutations in 45 patients, 24 previously described mutations in 89 patients) ascertained through heterozygotes from the analysis of 791 patients with definite, probable, or possible FH, mainly from the UK, using high‐throughput modifications of the single‐strand conformation polymorphism technique. From a composite database of LDL receptor gene mutations compiled from these two sets and from the literature, deductions are made about ascertainment bias, mutation rates, and molecular heterogeneity. Calculations suggest that there may be a large number of rare amino acid variants in the general population not causing classic FH. Approaches to, and feasibility of, molecular diagnostics are considered. Hum Mutat 10:116–127, 1997. © 1997 Wiley‐Liss, Inc.
Glycogenosis type II: A juvenile‐specific mutation with an unusual splicing pattern and a shared mutation in African AmericansAdams, Elizabeth M.; Becker, Jeffrey A.; Griffith, Linda; Segal, Ava; Plotz, Paul H.; Raben, Nina
doi: 10.1002/(sici)1098-1004(1997)10:2<128::aid-humu5>3.0.co;2-gpmid: 9259196
The recessively inherited deficiency of acid α‐glucosidase (GAA) called Glycogenosis Type II is expressed as three different phenotypes: infantile, juvenile, and adult. At the molecular level, infantile and adult forms of the disease have been extensively studied, but little is known regarding the genetic defects associated with the juvenile form. We describe a novel mutation that defines the intermediate juvenile phenotype in a compound heterozygous patient. A transversion of t to g in intron 6 at position –22 creates a cryptic acceptor site and results in unusual splicing abnormality: insertion of 21 nucleotides of the intronic sequence into mRNA and removal of exon 6 without disruption of the reading frame. The second mutation, Arg854Stop in exon 18, had been previously identified in another African‐American patient (Hermans et al., 1993a). Family study indicates that a silent allele harboring the Arg854Stop mutation in our patient is inherited from the patient's father, who is also African American, thus suggesting a common mutation in this population. Hum Mutat 10:128–134, 1997. © 1997 Wiley‐Liss, Inc.
Geographic distribution and regional origin of 272 cystic fibrosis mutations in European populationsEstivill, Xavier; Bancells, Consol; Ramos, Cristina
doi: 10.1002/(sici)1098-1004(1997)10:2<135::aid-humu6>3.0.co;2-jpmid: 9259197
The geographic distribution of 272 cystic fibrosis (CF) mutations has been studied by assessing the origin of 27,177 CF chromosomes from 29 European countries and three countries from the North of Africa. The 5 most common mutations are ΔF308 (66.8%), G542X (2.6%), N1303K (1.6%), G551D (1.5%) and W1282X (1.0%). The ΔF508 mutation has the highest relative frequency in Denmark (87.2%) and the lowest in Algeria (26.3%). Mutation G542X is common in the Mediterranean countries, with a mean frequency of 6.1%. N1303K is found in most of the western and Mediterranean countries and has the highest frequency in Tunisia (17.2%). The wide distribution of these mutations suggests an ancient origin. G551D is common in north‐west and central Europe, but is uncommon in other parts of Europe. W1282X has the highest frequency in Israel (36.2%), being also common in most Mediterranean countries and north Africa. Seventeen mutations have frequencies between 0.1 and 0.9%, 1717‐1G→A (0.83%), R553X (0.75%), R1162X (0.51%), 621+1G→T (0.54%) and 2183AA→G (0.36%), being the most common ones. Some mutations reach relatively high frequencies in some extended geographic regions, such as mutation 394delTT in northern Europe (1.1‐28.8%), R117H in northwestern Europe (1.3‐3.0%), R553X in central Europe (1.1‐24.4%), 1717‐1G→A in Belgium and France (1.1‐5.3%), and 2183AA→G in Italy and Greece (3.2%). Other mutations are only common in small regions: T338I (Sardinia), 711+1G→T (Tunisia), R1162X (Algeria and north of Italy), 1609delCA (east of Spain), 1811+1.6kbA→G (southeastern Spain), R1066C (Portugal), S549R (Algeria), R334W (Crete), 621+1G→T (Central Greece), 3849+10kbC→T (Israel), 2789+5G→A (south of Greece), 451+1G→A (Israel), R347P (south of Bulgaria), 1677delTA (south of Bulgaria and Turkey), G85E (south of Greece), R347H (Turkey), 3905insT (Switzerland), 1078delT (Brittany), 1898+1G→A (Wales), A455E (The Netherlands), ΔI507 (Brittany), 3659delC (Sweden) and R560T (northern Ireland). Most of these mutations must have an origin and diffusion in the specific European population subgroup. Overall 55 mutations are common in one or several countries or regions of Europe and 217 mutations are rare with relative frequencies of lower than 1% in any of these regions and countries. This information might facilitate mutation analysis of CF in the different regions of Europe. Hum Mutat 10:135–154, 1997. © 1997 Wiley‐Liss, Inc.
Familial ligand‐defective apolipoprotein B‐100: Simultaneous detection of the ARG3500→GLN and ARG3531→CYS mutations in a French populationRabès, JP; Varret, M; Saint‐Jore, B; Erlich, D; Jondeau, G; Krempf, M; Giraudet, P; Junien, C; Boileau, C
doi: 10.1002/(sici)1098-1004(1997)10:2<160::aid-humu8>3.0.co;2-opmid: 9259199
Familial ligand‐defective apolipoprotein B‐100 (FDB) is an autosomal dominant disorder leading to plasma LDL cholesterol elevation and coronary artery disease (CAD). Two specific mutations in the APOB gene—R3500Q and R3531C—induce FDB. We report an original method to detect both mutations simultaneously, based upon PCR‐mediated, site‐directed mutagenesis and double restriction of a unique PCR product. With this method we have investigated the prevalence of these mutations in 1,040 French patients. The R3500Q mutation was found in five probands. Genotypes were determined for 10 APOB polymorphic markers and were consistent with the common European ancestral haplotype previously reported. The only exception was one FDB proband who did not harbor the 48 repeat allele of the 3′HVR. Additionally, the first two R3531C mutations were identified in French probands. Genotypes were consistent with a previously reported haplotype, suggesting that this is another mutation of European ancestry. Hum Mutat 10:160–163, 1997. © 1997 Wiley‐Liss, Inc.