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PubMed1999

Adenosine deaminase polymorphisms at the protein and DNA levels.

Adenosine deaminase (ADA, E.C. 3.5.4.4) exhibits a well-known polymorphism at the protein level. We have studied ADA and an STR polymorphism exhibiting variation of a TTTA repeat motif at intron 3 of the ADA gene in random samples from northern Portugal (N = 218) and southwestern Germany (N = 114). The ADA phenotype distribution and population data on the worldwide distribution of ADA favor recurrent mutation as an explanation for the maintenance of the ADA*2 gene product at polymorphic frequencies.

Adenosine Deaminase↗

PubMed2000

Tracing European founder lineages in the Near Eastern mtDNA pool.

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

DNA, Mitochondrial↗

PubMed2002

Down-regulation and antiproliferative role of C/EBPalpha in lung cancer.

The transcription factor, CCAAT/enhancer binding protein alpha (C/EBPalpha) is important in the terminal differentiation of granulocytes, hepatocytes, and adipocytes, and recurrent mutations of C/EBPalpha were described in acute myeloid leukemia. In the lung, C/EBPalpha is expressed in bronchial cells and type II pneumocytes. Abnormal proliferation of the latter cell type was reported in C/EBPalpha knockout mice. We determined the expression of C/EBPalpha by Northern blot analysis in 30 lung cancer cell lines and found significant down-regulation in 24 cell lines. Immunohistochemical study of primary tumor specimens showed undetectable or low expression of C/EBPalpha in 23 of 53 specimens. Its expression was more frequently down-regulated in adenocarcinoma and poorly differentiated cancer specimens than in squamous cell cancers. A higher frequency of reduced expression was found in more advanced stages. To investigate the consequences of C/EBPalpha expression in lung cancer cells, we stably transfected two cell lines that do not express the gene (Calu1 and H358) with a plasmid allowing for induction of C/EBPalpha protein expression. Induction of C/EBPalpha led to significant growth reduction attributable to proliferation arrest, morphological changes characteristic of differentiation, and apoptosis. These results suggest that C/EBPalpha is down-regulated in a large proportion of lung cancers and that it has growth-inhibitory properties in airway epithelial cells. Genetic analysis of the C/EBPalpha gene is in progress to fully evaluate its role as a novel tumor suppressor in lung cancer.

Apoptosis↗

PubMed2002

Fine mapping of susceptibility genes by Lewontin's linkage disequilibrium measure with application to Alzheimer's disease.

OBJECTIVES: To formulate an equation for fine mapping of disease loci under complex conditions and determine the marker-disease distance in a specific case using this equation. METHODS: Lewontin's linkage disequilibrium (LD) measure D' was used to formulate an equation for mapping disease genes in the presence of phenocopies, locus heterogeneity, gene-gene and gene-environment interactions, incomplete penetrance, uncertain liability and threshold, incomplete initial LD, natural selection, recurrent mutation, high disease allele frequency and unknown mode of inheritance. This equation was then used to determine the distance between a marker ( epsilon 4 within the apolipoprotein E gene, APOE) and Alzheimer's disease (AD) loci using published data. RESULTS: An equation was formulated for mapping disease genes under the above conditions.If these conditions are present but ignored, then recombination fraction theta between marker and disease loci will be either overestimated or estimated with little bias. Therefore, an upper limit of theta can be obtained. AD has been found to be associated with the marker allele epsilon 4 in Africans, Asians, and Caucasians. This suggests that the AD- epsilon 4 allelic LD predates the divergence of peoples occurring 100 000 years ago. With the age of AD- epsilon 4 allelic LD so estimated, the maximal distance was calculated to be 23.2 kb (mean 5.8 kb). CONCLUSIONS: (1) A method is developed for LD mapping of susceptibility genes. (2) A mutation within the APOE gene itself, among others, is responsible for the susceptibility to AD, which is supported by recent evidence from studies using transgenic mice.

Alzheimer Disease↗

PubMed1994

Ionizing radiation and genetic risks. V. Multifactorial diseases: a review of epidemiological and genetic aspects of congenital abnormalities in man and of models on maintenance of quantitative traits in populations.

This paper discusses (a) data on the epidemiological and etiological aspects of human congenital abnormalities, (b) the multifactorial threshold model and other models which have been proposed to explain their inheritance patterns and recurrence risks in families and (c) current concepts on mechanisms on the prevalence of heritable variation for quantitative traits in populations. Congenital abnormalities, which afflict an estimated 6% of all live births, are etiologically heterogeneous. The majority of these do not follow Mendelian transmission patterns, but do 'run' in families. The multifactorial threshold model is an extension of genetic principles developed for quantitative traits to all-or-none traits; in its simplest formulation, it assumes the existence in the population of an underlying normally distributed 'liability' (which is due to numerous genetic and environmental factors acting additively, each contributing a small amount of liability) and of a 'threshold' beyond which the individual is affected. For most congenital abnormalities, the nature of these factors remains unknown. Other models assume fewer causal factors although, again, these remain to be identified. The question of how considerable heritable variation for most quantitative/polygenic traits has come to exist is a long-standing one in evolutionary population genetics. Models postulating that its existence is consistent with a balance between recurrent mutation and stabilizing selection or suggesting the possible operation of other mechanisms have been published in the literature. In the absence of knowledge on mechanisms responsible for the stable prevalences of congenital abnormalities or other multifactorial conditions in the population (but which is required to predict the consequences of an increase in mutation rate on their prevalences) it is necessary (a) to adapt and use concepts derived from quantitative and evolutionary population genetics and (b) to examine how sensitive the predictions are to the assumptions used, and how consistent they are with biological realities.

Abnormalities, Radiation-Induced↗

PubMed1994

A single engineered amino acid substitution changes antibody fine specificity.

During the acquisition of humoral immunity, the process of somatic hypermutation introduces nucleotide substitutions into expressed antibody (Ab) V region genes. Studies employing in vitro mutagenesis have shown that recurrent mutations observed in vivo often enhance the affinity of the target Ab for Ag. Here we show that a single amino acid replacement at position 35 in the H chain of an unmutated Ab with specificity for p-azophenylarsonate (Ars) confers specificity for the structurally related hapten p-azophenylsulfonate (Sulf) while abolishing specificity for Ars. The mutant Ab binds Sulf with an affinity characteristic of Ab produced by memory B cells. The same mutation in the somatically mutated anti-Ars Ab 36-71, for which the Fab crystal structure is known, resulted in a significant shift in fine specificity from Ars to Sulf. Examination of the crystal structure suggests that the specificity change is caused by a decrease in binding site size and/or new hydrogen bond geometry. Because the mutation at position 35 had been observed in somatically mutated Ab elicited by immunization with Ars followed by Sulf, the results confirm that somatic mutation in vivo can alter Ab specificity. The results also support the potential of Ab engineering to alter antigenic specificity.

Amino Acid Sequence↗

PubMed1997

Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.

An exacerbated genomic instability characterizes hereditary and sporadic gastrointestinal cancer of the microsatellite mutator phenotype (MMP), generating somatic frameshift mutations in genes containing mononucleotide repeats. We have recently shown that approximately 50, 40, and 30% of MMP+ colon tumors harbor frameshift mutations in (G)8, (A)8, and (C)8 tracks within the proapoptotic gene BAX and the hMSH3 and hMSH6 DNA mismatch repair genes, respectively. Here we report a higher incidence of frameshift mutations in these 3 genes in a panel of 25 MMP+ gastric adenocarcinomas: 64% in BAX and hMSH3, and 52% in hMSH6. These results support a multiple mutator gene model for the stepwise unfolding of the MMP and further illustrate the importance of the escape from apoptosis in gastrointestinal cancer. The tumor suppressor role played by BAX is also supported by the finding of other somatic BAX mutations, including recurrent missense mutations, not only in gastrointestinal cancer of the MMP but also in gastrointestinal cancer without the MMP.

Apoptosis↗

PubMed1998

A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.

The polymorphism G20210A in the 3' untranslated region of the prothrombin gene is associated with an increased level of factor II activity and confers a twofold to fivefold increase in the risk for venous thromboembolism. Among Caucasian populations, the prevalence of factor II G20210A heterozygotes is 1% to 6%, whereas in non-Caucasian populations it is very rare or absent. The aim of the present study was to discern whether factor II G20210A originated from a single or recurrent mutational events. Allele frequencies of four dimorphisms spanning 16 of 21 kb of the factor II gene were determined in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II G20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (P = .0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and only in 34% of 20210G normal alleles (P < .0001). These data strongly support a single origin for factor II G20210A that probably occurred after the divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.

Africa, Northern↗

PubMed1997

Non random DNA evolution.

A model for testing random molecular evolution is proposed. Randomness of recurrent mutation is defined based on isotropy and zero covariance among nucleotide sites. Assuming an equal rate of mutation for the bases A, T, G, and C, in both DNA strands, a mutational matrix of transformation A, T, G, and C with 6 parameters is developed. Under this model the equilibrium proportions (F) of the bases are FA = FT = (D + E)/[2(D + E + H + J)] and FG = FC = (H + J)/[2(D + E + H + J)], D, E, H, J being 4 of the 6 matrix parameters. Thus the expected (FA + FT)/(FG + FC) ratio can also be tested. If the average rate of mutation is 10(-8) per nucleotide site and cell replication, the equilibrium for every site, in most species, is reached in 10(8) years. Eight DNA segments from human, bacteria, fungus and insect genomes were chosen to test these proportions and their heterogeneity among coding and non coding subsegments. While FG was similar to FC as expected, FA was highly different from FT Huge heterogeneities were found between coding and non coding segments and among non coding segments. These results are a strong evidence for non randomness of molecular evolution.

Animals↗

PubMed2002

Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.

BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families.

Adult↗

PubMed2001

The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation.

The most recurrent BRCA1/BRCA2 mutation in Sweden is the BRCA1 mutation 3171ins5. In the western part of Sweden this mutation accounts for as much as 77% of identified mutations in these two genes. Our aim was to analyse in detail the haplotype and founder effects of the 3171ins5 and furthermore attempt to estimate the time of origin of the mutation. In the study we included eighteen apparently unrelated families with hereditary breast and/or ovarian cancer. At least one individual in each family had previously tested positive for the 3171ins5 mutation. Polymorphic microsatellite markers were used for the haplotype analyses. The markers were located within or flanking the BRCA1 gene spanning a region of 17.3 cM. We found several different haplotypes both for disease alleles and for the normal alleles. However, a conserved haplotype of 3.7 cM was observed in the 3171ins5 carriers spanning over four markers located within or very close to the BRCA1 gene. As this haplotype was not present in any of the normal controls it is highly likely that this is a mutation identical by descent, i.e. a true founder. The results from the haplotype analyses were used to estimate the age of the mutation. Estimations based on the P(excess) and linkage disequilibrium gives a first appearance of the mutation sometime around the 6th century, approximately 50 generations ago.

BRCA1 Protein↗

PubMed2006

Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins.

Localized autosomal recessive hypotrichosis (LAH) is rare disorder affecting the scalp, trunk and extremities and largely sparing the facial, pubic and axillary hair. Mutations in desmoglein 4 (DSG4) gene are responsible for LAH which maps to human chromosome 18q12. In this study a recurrent intragenic deletion mutation (Ex5_8del) was identified in DSG4 gene in two Pakistani families of Balochi and Sindhi origins. Manifestation of identical intragenic deletion mutation in eight Pakistani families, six reported earlier and two here, is exceptionally evocative of the dispersion of ancestral chromosome in different ethnic groups through common ancestors.

Base Sequence↗

PubMed1998

A recurrent glycine substitution mutation, G2043R, in the type VII collagen gene (COL7A1) in dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). Nearly all cases of dominant DEB are caused by glycine substitution mutations occurring within the triple helical region of type VII collagen, and most of the mutations are unique to individual families. In this study, we identified a patient of Hispanic-Mexican origin with a mild form of DEB, which resulted from a de novo dominant glycine substitution, G2043R, in exon 73 of COL7A1. We also investigated a Scottish family with a three-generation pedigree of dominant DEB, in whom the same glycine to arginine substitution mutation was demonstrated. This particular mutation has also been detected previously in three other families with dominant DEB: one Italian, one Hungarian and one Norwegian. Given the widespread geographical distribution of this mutation and the demonstration of its occurrence as a de novo event, G2043R therefore represents the first example of a mutational hotspot in dominant DEB. Interestingly, although both the Mexican and Scottish families we studied had some clinical features in keeping with the Pasini form of the disorder, there was considerable interfamilial variability as well as intrafamilial diversity in the affected individuals.

Adult↗

PubMed2003

Recurrent de novo mitochondrial DNA mutations in respiratory chain deficiency.

Starting from a cohort of 50 NADH-oxidoreductase (complex I) deficient patients, we carried out the systematic sequence analysis of all mitochondrially encoded complex I subunits (ND1 to ND6 and ND4L) in affected tissues. This approach yielded the unexpectedly high rate of 20% mutation identification in our series. Recurrent heteroplasmic mutations included two hitherto unreported (T10158C and T14487C) and three previously reported mutations (T10191C, T12706C and A13514G) in children with Leigh or Leigh-like encephalopathy. The recurrent mutations consistently involved T-->C transitions (p<10(-4)). This study supports the view that an efficient molecular screening should be based on an accurate identification of respiratory chain enzyme deficiency.

Adolescent↗

PubMed2026

Mutational signature stratification of recurrent gliomas reveals distinct patterns of genomic traits.

BACKGROUND: Although temozolomide (TMZ) is widely used for glioma treatment, its therapeutic benefit is limited by acquired resistance and recurrence, facilitated by intratumor heterogeneity. Mutational signatures (MSs) inform tumor evolution and reveal alterations associated with treatment response. METHODS: We performed molecular analyses of 96 glioma recurrences with sufficient private single-nucleotide variants relative to their matched primary tumors, stratified by their dominant MS. RESULTS: Four groups were identified: MS11/TMZ-related (n = 38), MS1/5/aging-related (n = 32), MS6/15/21/26/microsatellite instability (MSI)-related (n = 13), and other MS-related recurrences (n = 13). MS11/TMZ-related recurrences showed higher acquired mutational counts than the other groups (1338 vs 59 (MS1/5/aging) vs 57 (MS6/15/21/26/MSI) vs 57 (other MSs); P < .01). Mutations in SYNE2, SZT2, and FBN3 were restricted to recurrences with dominant or second-dominant MS11/TMZ-related signature (n = 41), and 85% (35/41) harbored mutations in these genes. In MS11/TMZ-related recurrences with RNA sequencing data (n = 17), mRNA co-expression analyses identified SYNE2-ATAD5 and SZT2-MAPKBP1 associations. Among MS11/TMZ-related recurrences, MS23 was frequent (44%, 18/41) and associated with higher acquired mutational counts (2089 vs 1188; P = .018) and more IDH-wildtype tumors (67% vs 30%; P = .037). MAPKBP1 mutations were enriched in MS23-positive recurrences (56% (10/18) vs 0% (0/23); P < .001). MS1/5/aging-related recurrences showed more frequent acquired chromosome 16q losses (22% vs 8% (TMZ) vs 0% (MSI) vs 0% (other); P < .05), which were associated with an increased fraction of genome altered relative to 16q-diploid cases (15% vs 7%; P = .01). CONCLUSIONS: These findings show that MS-based stratification of recurrences refines molecular characterization after therapy and nominates candidate biomarkers and pathways for functional studies of treatment-associated glioma evolution.

mutational signatures↗

PubMed2004

NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.

BACKGROUND: Mutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations. METHODS: NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS). RESULTS: Twenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases. CONCLUSION: Patients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation.

Age of Onset↗

PubMed2001

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Age of Onset↗

PubMed2002

A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene.

Spinal neurofibromas are found in up to 38% of NF1 patients. However, they cause clinical implications only in about 5% of the patients. In contrast, multiple symptomatic spinal neurofibromas are the main clinical finding in patients with familial spinal neurofibromatosis. Familial spinal neurofibromatosis has been considered to be a distinct clinical form of neurofibromatosis. Linkage analysis in two families and identification of a NF1 gene mutation in a third family strongly associate spinal neurofibromatosis with the NF1 gene. We describe a NF1 patient who satisfies the NIH diagnostic criteria and has severe spinal involvement with bilateral spinal root neurofibromas at every level. A recurrent splice site mutation (IVS19b-3C>G) was identified in the NF1 gene in the patient. We discuss the possibility that the clinical picture of this patient represents an additional example of spinal neurofibromatosis. By comparison of the clinical expression of NF1 in this patient and that in another patient with the identical mutation the hypothesis that spinal neurofibromatosis is associated with a particular mutation is highly unlikely. The involvement of other genes linked to the NF1 gene or modifying genes is currently the most likely explanation for the clinical phenotype of spinal neurofibromatosis.

Adult↗