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At least 235 records · Page 13Linked to original sources
PubMed1997

Enhanced restriction site mutation (RSM) analysis of 1,2-dimethylhydrazine induced mutations, using endogenous p53 intron sequences.

The restriction site mutation (RSM) assay was used to study the mutational sensitivities of three target regions of the murine p53 gene. The non-coding intron 6 target region was compared with the coding regions exon 4 and exon 5 with respect to their relative sensitivity to the induction of mutations by 1,2-dimethylhydrazine (DMH). Our results demonstrated that the majority of induced mutations detected were in the intron 6 gene region. A total of 15 enzyme-resistant restriction sites were detected in DMH treated mice, nine of these in the intron 6 region, four in the exon 4 region and two in the exon 5 region. The elevated sensitivity of the intron 6 region was exemplified by our detection of spontaneous mutations in this region; two resistant restriction sites were detected in untreated animals. No spontaneous mutations were detected in either of the exon sequences studied here, nor have any been detected in exon targets in our previous in vivo RSM analyses. The mutations induced by DMH were mostly GC-->AT transitions, as were the spontaneous mutations identified. The mutation frequencies calculated by the inclusion of a mutant internal standard (MIS) in the RSM method, revealed that the non-coding intron 6 region and the exon 4 region had a 10-fold higher mutation frequency than the exon 5 region. This heterogenous distribution of mutations and their differential mutation frequencies, were probably a consequence of the greater selection in the coding regions in p53 function. However, the actual mechanism of differential mutation induction is, as yet, to be defined.

1,2-Dimethylhydrazine↗
PubMed1993

General cystic fibrosis mutations are usually missense mutations affecting two specific protein domains and associated with a specific RFLP marker haplotype.

Some 250 different mutations have so far been screened in the cystic fibrosis (CF) gene. The 50 nonsense, 33 splicing and 60 frameshift mutations are randomly distributed within the gene, unlike the 107 missense mutations or amino acid deletions. A large excess of missense mutations affects the exons encoding the first transmembrane (MS1) and first ATP-binding fold (NBF1) domains. Sixty-four of the 107 missense mutations may be classified as private, demic, local and general mutations on the basis of their geographic distribution in Europe. Private and demic mutations are randomly distributed within the gene; local and general mutations are not. It is well known that some RFLP markers are in linkage disequilibrium with some mutations. Private, demic and local mutations are randomly associated with each class of RFLP haplotypes. In contrast, general mutations, frequent and infrequent, are not randomly associated with RFLP markers. General mutations usually affect a specific part of the gene and are more likely to be associated with a specific RFLP marker. This suggests the existence of selective factors favoring these mutations, a hypothesis formerly postulated as a possible cause of the high frequency of the disease.

Cystic Fibrosis↗
PubMed1998

A new point mutation (3426, A to G) in mitochondrial NADH dehydrogenase gene in Korean diabetic patients which mimics 3243 mutation by restriction fragment length polymorphism pattern.

Mitochondrial tRNA(Leu)(UUR) gene mutation is one of the candidates in the pathogenesis of NIDDM. Especially the 3243 (A-->G) mutation is associated with the maternally-inherited diabetes and deafness. To evaluate the prevalence and characteristics of the 3243 point mutation in Koreans, we screened 433 Korean diabetic patients (220 men and 213 women). Genomic DNA was extracted from peripheral white blood cells and PCR was carried out with mitochondrial DNA primers (3130-3149, 3558-3539) encompassing the 3243 position. After digestion with Apa-1, five subjects showed polymorphism suggesting 3243 point mutation but when we directly sequenced the amplified DNA with an automatic sequencer, only 2 of the 5 patients were shown to have 3243 (A-->G) mutation and the other 3 subjects had 3426 (A-->G) mutation rather than 3243 mutation. Two diabetic patients with 3243 mutation were lean (BMI = 14.4, 17.0 kg/m2), had relatively lower fasting C-peptide concentrations (0.9 ng/ml each), and required insulin for management. In contrast, those with 3426 point mutation were not lean (BMI = 22.6-28.0 kg/m2), had relatively higher C-peptide levels (3.9-5.4 ng/ml), and could be managed with oral hypoglycemic agents. None of the 5 patients had deafness. In conclusion, the prevalence of 3243 point mutation in Korean diabetic patients was approximately 0.5% and we found a new mutation mimicking 3243 mutation by PCR-RFLP (restriction fragment length polymorphism) pattern. We suggest that sequencing of the PCR product or designing smaller PCR fragment size to enhance the specificity may help to identify the exact location of the point mutation.

Adult↗
PubMed1999

Influence of polymorphism at p53, CYP1A1 and GSTM1 loci on p53 mutation and association of p53 mutation with prognosis in lung cancer.

BACKGROUND: We previously found that the majority (9/11) of p53 tumor suppressor gene mutations in 60 lung cancer patients in Taiwan were small intragenic deletions and nonsense mutations. To gain insights into the possible etiologic factors involved in these mutations and the prognostic significance of p53 gene mutations in lung cancer in Taiwan, we investigated the influence of polymorphism at p53, cytochrome p450 1A1 (CYP1A1) and glutathione S-transferase M1 (GSTM1) loci on p53 gene mutation, and the association of p53 gene mutation with prognosis in these lung cancer patients. METHODS: The polymorphism of these genes was determined by polymerase chain reaction followed by restriction enzyme digestion. The Pearson chi 2 test was used to compare allelic distributions between lung cancer patients and controls. The log-rank test was used to assess the significance of the survival differences between patients with and without p53 mutations. RESULTS: There was no significant difference with respect to the genotype distribution of p53, CYP1A1 and GSTM1 polymorphisms between patients with and without p53 mutations, although a tendency toward increasing frequency of the wild-type homozygote genotype of p53 polymorphism was noted in lung cancer patients containing p53 mutations. We further analyzed the association of p53 mutation with prognoses in lung cancer patients for whom postoperative survival data were available. The estimated median survival times for patients with and without p53 mutation were 25 and 28 months, respectively. There was no significant correlation between p53 mutation and survival. CONCLUSIONS: Our data suggest that p53 gene mutation may not be associated with polymorphisms of p53, CYP1A1 and GSTM1 genes, and it may have no significant effect on the prognosis of lung cancer patients in Taiwan.

Chromosome Mapping↗
PubMed2001

Nontruncating APC germ-line mutations and mismatch repair deficiency play a minor role in APC mutation-negative polyposis.

Familial adenomatous polyposis, an autosomal-dominantly inherited colorectal cancer predisposition syndrome, is caused by germ-line mutations in the adenomatous polyposis coli (APC) gene. Despite the use of different screening methods, studies worldwide fail to identify APC mutations in 20-50% of all familial adenomatous polyposis patients (APC mutation-negatives). In this study, missense mutations in the coding region of the APC gene, which would have been missed by the protein truncation test, as well as mutations in the APC promoter and the 3' untranslated region, were determined by the single nucleotide polymorphism discovery assay and direct DNA sequencing in 31 mutation-negative polyposis patients. Seventeen gene alterations were identified, whereof four (12.9%) represent possibly pathogenic germ-line mutations: silent A290T (promoter) and A8822G (3' untranslated region) as well as missense R99W and E1317Q (coding region). The 27 remaining, truly APC mutation-negative polyposis patients displayed a significantly later age at diagnosis compared with APC mutation carriers (46.1 versus 35.2 years; P < 0.01). APC mutation-negative individuals with >100 colonic polyps were more likely to present with extracolonic disease (P < 0.05) than those with <100. Assessment of microsatellite instability (MSI), a hallmark of mismatch repair deficiency, in 68 tumors from 21 truly APC mutation-negative patients, identified 4 (5.9%) unstable tubulo-villous adenomas (3 MSI-High and 1 MSI-Low), stemming from 4 (19%) unrelated individuals and likely to be caused by hMLH1 promoter hypermethylation. In conclusion, only a small proportion of APC germ-line mutation carriers is missed by the protein truncation test, and mismatch repair deficiency does not seem to substantially contribute to tumor development in APC mutation-negative polyposis patients.

3' Untranslated Regions↗
PubMed1998

Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses.

Dominant mutations in three fibroblast growth factor receptor genes (FGFRs1-3) cause Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. In the present study, 50 Brazilian patients with these four syndromes (27 Apert, 17 Crouzon, 5 Pfeiffer, and 1 Jackson-Weiss patients) were screened for mutations in the FGFR1-3 genes. Except for one, all the Apert patients had either S252W (n = 16) or P253R (n = 10) mutations. The remaining Apert case is atypical with a mutation altering the splice site of FGFR2 exon IIIc. The Pfeiffer patients had mutations in one of the FGFR genes: three in FGFR2, one in FGFR1, and one in FGFR3. In contrast, only 8 of the 17 Crouzon patients studied had a mutation in either FGFR2 (n = 7) or FGFR3 locus (n = 1). Mutations in the FGFR2 locus account for most (93%) of our syndromic craniosynostotic cases, whereas 5% had mutations in the FGFR3 locus and only 2% had mutations in the FGFR1 gene. Except for one, all the other mutations were reported previously in craniosynostotic patients from other populations. Interestingly, the mutation C278F, previously described in Crouzon and Pfeiffer cases, was here identified in a familial case with Jackson-Weiss. Also, unexpectedly, a common mutation altering the splice site of the FGFR2 exon IIIc was found in one Apert and two Pfeiffer patients. In addition, we identified a new mutation (A337P) in the FGFR2 exon IIIc associated with Crouzon phenotype.

Acrocephalosyndactylia↗
PubMed1998

Requisite mutational load, pathway epistasis and deterministic mutation accumulation in sexual versus asexual populations.

A measure of the equilibrium load of deleterious mutations is developed that explicitly incorporates the level of genome-wide linkage disequilibrium. This measure, called the requisite mutational load, is based on the minimal net reproductive rate of the least mutated class necessary to prevent the deterministic mutation accumulation. If this minimal net reproductive rate is larger than ecological or physiological constraints allow, then: a) the population is driven to extinction via deterministic mutation accumulation, or b) a mutational Red-Queen ensues with adaptation counterbalancing mutation accumulation. Two population parameters determine the requisite mutational load: a) the equilibrium strength of selection, measured as a selection gradient, and b) the equilibrium opportunity for selection, measured as the variance in number of mutations per genome. The opportunity for selection is decomposed into the accumulation of mutations (average number per genome) and the level of genome-wide linkage disequilibrium. Recombination can substantially reduce the requisite mutational load, compared to clonal reproduction, when there is buffering and/or reinforcing epistasis and also when there is positive assortative mating for fitness. Recombination is advantageous because it reduces the negative (variance reducing) linkage disequilibrium induced by beneficial epistasis. The functional form of the expression for requisite mutational load illustrates why epistasis within pathways, i.e., among closely interacting genes, is a powerful alternative to genome-wide truncation selection, as a means of reducing mutational load.

Animals↗
PubMed1999

Identification of four novel mutations of the XLRS1 gene in Japanese patients with X-linked juvenile retinoschisis. Mutation in brief no. 234. Online.

The XLRS1 gene (HUGO-approved symbol, RS1) has been found to cause X-linked recessive retinoschisis (RS) which is characterized by splitting of the superficial layer of the retina. Recent mutation analysis of this gene revealed 82 different mutations in 214 patients with RS. We have now identified 10 mutations of the XLRS1 gene in 11 unrelated Japanese males with RS. Mutations found in these patients were; 1) a 20-kb deletion in exon 1 region; 2) mutations in the initiation sequence (M1V); 3) mutations in the splice donor site (IVS1 + 1 g-->a); 4) two nonsense mutations (Q88X, W163X); and 5) five missense mutations (E72K, Y89C, R182C, G109E, P203L). Four (M1V, Q88X, G109E, and W163X) of the 10 mutations were novel. The R182C mutation was identified in 2 unrelated patients. The 3 mutations found between exons 1 and 3 cause premature translation termination in the XLRS1 protein. The rest of the 7 mutations were clustered between exons 4 and 6. This region of the protein is homologous to the proteins implicated in cell-cell adhesion.

Cell Adhesion↗
PubMed2002

Detection of C1 inhibitor (SERPING1/C1NH) mutations in exon 8 in patients with hereditary angioedema: evidence for 10 novel mutations.

Hereditary angioedema (HAE) is caused by mutations in the C1 inhibitor gene (SERPING1, C1NH) and the result is C1 inhibitor deficiency, either in levels or function. We have searched exon 8 for mutations by direct sequencing and analyzed the rest of the exons by SSCP in 87 Spanish families affected by HAE. Out of 87 screened families, we have detected exon 8 mutations in 26. Among these, 17 different mutations were identified: 14 point mutations and 3 frameshift. Seven of the point mutations and the three frameshift were not previously reported. Mutations were: S438P; R444P; V451G; W460X; V468D; G471E; X479R; S417fsX427; I440fsX450; E429fsX450. The rest of the families presented previously reported mutations, 5 missense and two nonsense. In none of the 26 families was an additional change identified in the rest of the exons by SSCP, and, in 20 out of the 22 families with point mutation, we verified that the mutation did not affect a healthy relative. Seven of these families had no history of the disease, and in five of them we were able to verify that the progenitors did not have the mutation. Therefore, they were de novo mutations.

Angioedema↗
PubMed1999

Detection of the most common G6PD gene mutations in Chinese using amplification refractory mutation system.

Glucose-6-phosphate dehydrogenase (G6PD) is the most common human enzymopathy. To date more than 122 mutations in the G6PD gene have been discovered, among which 12 point mutations are found in the Chinese. The 2 most common mutations, G1388A and G1376T, account for more than 50% of mutations representing various regions and ethnic groups in China. Setting up a simple and accurate method for detecting these mutations is not only useful for studying the frequency of the G6PD genotypes, but also for finding new mutations. The purpose of this study was to find a simple, inexpensive and accurate method for detecting these common mutations. The amplification refractory mutation system (ARMS) method was used in this study. Samples from 28 G6PD-deficient males were investigated. The natural and mismatched amplification and restriction enzyme digestion method was used as a standard method to evaluate the nature of the point mutations. Sixteen cases were found carrying the G1388A mutation and 12 the G1376T mutation. Fourteen cases of G1388A and 10 cases of G1376T were confirmed by ARMS. Four cases were not in concordance with the results obtained by the mismatched amplification-restriction enzyme digestion. These 4 cases were then judged by direct PCR sequencing at exon 12. The DNA sequencing data supported the results obtained by ARMS. Thus we concluded that the ARMS is a rapid, simple, inexpensive and accurate method for detecting the most common G6PD gene mutations among the Chinese.

Asian People↗
PubMed2006

Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations.

Fabry disease, an X-linked recessive inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal exoglycohydrolase, alpha-galactosidase A (EC 3.2.1.22; alpha-Gal A). The molecular lesions in the alpha-Gal A gene causing the classic phenotype of Fabry disease in 66 unrelated families were determined. In 49 families, 50 new mutations were identified, including: 29 missense mutations (N34K, T41I, D93V, R112S, L166G, G171D, M187T, S201Y, S201F, D234E, W236R, D264Y, M267R, V269M, G271S, G271V, S276G, Q283P, A285P, A285D, M290I, P293T, Q312H, Q321R, G328V, E338K, A348P, E358A, Q386P); nine nonsense mutations (C56X, E79X, K127X, Y151X, Y173X, L177X, W262X, Q306X, E338X); five splicing defects (IVS4-1G>A, IVS5-2A>G, IVS5+3A>G, IVS5+4A>G, IVS6-1G>C); four small deletions (18delA, 457delGAC, 567delG, 1096delACCAT); one small insertion (996insC); one 3.1 kilobase Alu-Alu deletion (which included exon 2); and one complex mutation (K374R, 1124delGAG). In 18 families, 17 previously reported mutations were identified, with R112C occurring in two families. In two classically affected families, affected males were identified with two mutations: one with two novel mutations, D264Y and V269M and the other with one novel (Q312H) and one previously reported (A143T) mutation. Transient expression of the individual mutations revealed that D264Y and Q312H were localised in the endoplasmic reticulum and had no detectable or markedly reduced activity, whereas V269M and A143T were localised in lysosomes and had approximately 10 per cent and approximately 35 per cent of expressed wild-type activity, respectively. Structural analyses based on the enzyme's three-dimensional structure predicted the effect of the 29 novel missense mutations on the mutant glycoprotein's structure. Of note, three novel mutations (approximately 10 per cent) were predicted not to significantly alter the glycoprotein's structure; however, they were disease causing. These studies further define the molecular heterogeneity of the alpha-Gal A mutations in classical Fabry disease, permit precise heterozygote detection and prenatal diagnosis, and provide insights into the structural alterations of the mutant enzymes that cause the classic phenotype.

Base Sequence↗
PubMed1982

Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea.

In a combined experiment, dominant cataract mutations and specific-locus mutations were scored in the same offspring. In radiation experiments, a total of 15 dominant cataract and 38 specific-locus mutations was scored in 29396 offspring. In experiments with ethylnitrosourea (ENU), a total of 12 dominant cataracts and 54 specific-locus mutations was observed in 12712 offspring. The control frequency for dominant cataracts was 0 in 9954 offspring and for specific-locus mutations 11 in 169955 offspring. The ratio of radiation-induced recessive visible to dominant mutations was about 2.5:1. The difference was even more pronounced for ENU-induced mutations. The ratio of recessive visibles to dominant cataracts for chemically induced mutations in spermatogonia was about 5.4:1. The two characteristic features of radiation-induced specific-locus mutations--the augmenting effect of dose fractionation and the quantitative differences in the mutation rates between spermatogonial and post-spermatogonial stages--can also be demonstrated for the induction of dominant cataracts. The dominant cataract mutations recovered can be categorized into 7 phenotypic classes: total opacity, nuclear and zonular cataract, nuclear cataract, anterior pyramidal cataract, anterior polar cataract, anterior capsular cataract, and vacuolated lens. The largest class of mutations, a total of 11, affected the anterior polar region, while the number of total opacities in both experiments was 5. The only noteworthy difference observed between the radiation- and ENU-induced mutations recovered was that, of the 2 radiation-induced total lens opacities, both were associated with an iris anomaly and microphthalmia whereas the ENU-induced total opacities were not.

Animals↗
PubMed1996

A novel lacI transgenic mutation-detection system and its application to establish baseline mutation frequencies in the scid mouse.

To assess DNA mutations in vivo, we have established a new transgenic mouse line, BC-1, carrying a lacI target gene for mutation detection within a bacteriophage shuttle-vector. The lacI gene was positioned within sequences derived from a rearranged murine immunoglobulin gene locus, a feature that distinguishes the BC-1 transgene from other shuttle vector systems. As mutations in lacI transgenes likely reflect mutations occurring throughout the genome, these systems have been successfully used to investigate spontaneous and induced mutations in a variety of tissues. An important additional application of the transgenic systems is the characterization of lacI mutations occurring in murine strains having specific DNA repair defects. For this study, scid (severe combined immunodeficiency) mice were selected as animals with this mutation have a defect in double-strand DNA break repair. To determine what impact the scid mutation might have on spontaneous mutation frequencies within DNA recovered from various tissues, these mice were crossed with the BC-1 line. Interestingly, mutation frequencies within BC-1/scid mouse DNA were not significantly different from those of BC-1 control mice. Furthermore, spontaneous lacI mutations obtained from BC-1 and from BC-1/scid liver DNA were similar in spectrum. As spontaneous BC-1 liver mutations were similar to those reported previously for other lacI systems, such as the Big Blue transgenic line, this suggested that the nature of the DNA sequences flanking the reporter gene did not modify lacI mutation rate or character.

Animals↗
PubMed2000

Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation.

Missense and splicing point mutations have been found in the tau gene in families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Of these mutations, we examined four exonic missense point mutations (G272V, P301L, V337M and R406W) in 3-repeat or 4-repeat tau isoform on the transfection experiment. The effects of two mutations (G272V or P301L) on microtubules were subtle whereas those of two other mutations (V337M or R406W) were dramatically significant when these two mutations were constructed into 3-repeat tau but not into 4-repeat tau. The R406W mutation induced an alternation of microtubules to form dotted or fragmented forms retaining colocalization of tau with tubulin whereas the V337M mutation predominantly disrupted microtubule networks and diminished colocalization of tau and tubulin. The effect of the mutations on microtubules were thus site-dependent and isoform-dependent. Tau with R406W mutation was found to be colocalized with tubulin without filamentous structures on confocal views, suggesting that the carboxyl region of tau played a different role from tubulin-binding domain on microtubule assemble. Another abnormal property was identified in tau with R406W mutation that failed to suffer phosphorylation. Thus, diverse effects of tau mutations on microtubules may explain the various clinicopathologies of FTDP-17 and related tauopathies.

Animals↗
PubMed1999

Screening for mutations in the uroporphyrinogen decarboxylase gene using denaturing gradient gel electrophoresis. Identification and characterization of six novel mutations associated with familial PCT.

The two porphyrias, familial porphyria cutanea tarda (fPCT) and hepatoerythropoietic porphyria (HEP), are associated with mutations in the gene encoding the enzyme uroporphyrinogen decarboxylase (UROD). Several mutations, most of which are private, have been identified in HEP and fPCT patients, confirming the heterogeneity of the underlying genetic defects of these diseases. We have established a denaturing gradient gel electrophoresis (DGGE) assay for mutation detection in the UROD gene, enabling the simultaneous screening for known and unknown mutations. The established assay has proved able to detect the underlying UROD mutation in 10 previously characterized DNA samples as well as a new mutation in each of six previously unexamined PCT patients. The six novel UROD mutations comprise three missense mutations (M01T, F229L, and M324T), two splice mutations (IVS3-2A-->T and IVS5-2A-->G) leading to exon skipping, and a 2-bp deletion (415-416delTA) resulting in a frameshift and the introduction of a premature stop codon. Heterologous expression and enzymatic studies of the mutant proteins demonstrate that the three mutations leading to shortening or truncation of the UROD protein have no residual catalytic activity, whereas the two missense mutants retained some residual activity. Furthermore, the missense mutants exhibited a considerable increase in thermolability. The six new mutations bring to a total of 29 the number of disease-related mutations in the UROD gene. The DGGE assay presented greatly improves the genetic diagnosis of fPCT and HEP, thereby facilitating the detection of familial UROD deficient patients as well as the discrimination between familial and sporadic PCT cases.

Alleles↗
PubMed2005

Identification of 14 novel mutations in DHCR7 causing the Smith-Lemli-Opitz syndrome and delineation of the DHCR7 mutational spectra in Spain and Italy.

The Smith-Lemli-Opitz syndrome (SLOS) is a phenotypically variable metabolic malformation and mental retardation syndrome for which more than 80 mutations in the DHCR7 disease-causing gene have been described. The DHCR7 mutational spectra differ significantly in different areas of Europe, and several common putative founder mutations account for a substantial fraction of all mutations in some ethnic groups. Here we have analysed 47 SLOS patients and describe 14 newly identified mutations in 18 SLOS patients of Ashkenazi Jewish, Austrian, British, German, Italian, Irish, Polish, Portuguese, and Spanish origins. Half of the new mutations are in the transmembrane domains of the protein. In addition, there were two null mutations, one mutation in the 4th cytoplasmic loop, two mutations in the first and last codons, and three mutations in other regions such as the second cytoplasmic loop and the first endoplasmic loop. The analysis included 20 Spanish and 12 Italian SLOS patients and revealed very different mutation spectra in these patients compared to previously described patients from Czechoslovakia, Germany, Poland, and the UK and implicated p.Thr93Met on the J haplotype as the most frequent Mediterranean founder mutation.

Adolescent↗
PubMedDate not supplied

Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands.

Sequencing of HFE exons 2, 3, 4, and 5, and of portions of introns 2, 4, and 5 revealed novel mutations in four of twenty hemochromatosis probands who lacked C282Y homozygosity, C282Y/H63D compound heterozygosity, or H63D homozygosity. Probands 1 and 2 were heterozygous for previously undescribed mutations: exon 2, nt 314T-->C (314C; I105T), and exon 2, nt 277G-->(277C; G93R), respectively; these probands were also heterozygous for H63D and C282Y, respectively. Probands 3 and 4 were heterozygous for a previously described but uncommon HFE mutation: exon 2, nt 193A-->T (193T; S65C). Proband 3 was also heterozygous for C282Y and had porphyria cutanea tarda, and Proband 4 had hereditary stomatocytosis. Each of these four probands had iron overload. In each proband with an uncommon HFE coding region mutation, I105T, G93R, and S65C occurred on separate chromosomes from those with the C282Y or H63D mutations. Neither I105T, G93R, nor S65C occurred as spontaneous mutations in our probands. The I105T and G93R mutations were linked to haplotypes bearing HLA-A3,-B7 and HLA-A2,-B62, respectively. The S65C mutation was linked to a haplotype characterized by HLA-32. Sixteen other probands did not have an uncommon HFE exon mutation. In 176 normal control subjects, two were heterozygous for S65C, but I105T and G93R were not detected. Nine of twenty probands were heterozygous and two probands were homozygous for a previously described base-pair change at intron 2, nt 3671T-->C. One proband without a detectable missense mutation had a previously described intron 5 allele (nt 6700G-->A). Heterozygosity for a previously described base-pair change in intron 4 (nt 5636T-->C) was detected in all persons we studied who also had the S65C mutation. One proband was heterozygous for a previously undescribed base-pair change at intron 5 (nt 5807A-->G). We conclude that uncommon HFE exon and intron mutations may be discovered among hemochromatosis patients who have "atypical" HFE genotypes.

Adult↗
PubMed2001

Frequency gradients of DHCR7 mutations in patients with Smith-Lemli-Opitz syndrome in Europe: evidence for different origins of common mutations.

Smith-Lemli-Opitz syndrome/RSH (SLOS) is a multiple congenital anomaly syndrome caused by mutations in the gene for Delta7-sterol reductase (DHCR7) which catalyses the last step in the biosynthesis of cholesterol. SLOS is among the common recessive disorders in Europeans but almost absent in most other populations. More than 40 mutations in the DHCR7 gene some of which are frequent have been described in SLOS patients of various origins. Here we report mutation analysis of the DHCR7 gene in SLOS patients from Poland (n = 15), Germany/Austria (n = 22) and Great Britain (n = 22). Altogether 35 different mutations were identified and the two null mutations IVS8-1G > C and W151X were the most frequent in the total sample. In all three populations three mutations accounted for >0.5 of SLOS chromosomes. The mutational spectra were, however, significantly different across these populations with each of the common mutations showing an east-west gradient (W151X, V326L) or vice versa (IVS8-1G > C). W151X is the most frequent (0.33) mutation in Polish SLOS patients. It has an intermediate frequency in German/Austrian patients (0.18) and is rare among British patients (0.02). V326L shows the same distribution pattern (Poland 0.23, Germany/Austria 0.18, Britain 0.02). In contrast IVS8-1G > C is most frequent in Britain (0.34) intermediate in Germany/Austria (0.20) and rare in Poland (0.03). All analysed IVS8-1G > C and V326L alleles shared the same DHCR7 haplotype, whereas the W151X mutation occurred on different haplotypes. There is evidence for both recurrent mutations and founder effects. Together this suggests that the common SLOS mutations in Europe have different geographic and historic origins and spread across the continent in opposite directions.

Alleles↗