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PubMed1995

Monoallelic mutation analysis (MAMA) for identifying germline mutations.

Dissection of germline mutations in a sensitive and specific manner presents a continuing challenge. In dominantly inherited diseases, mutations occur in only one allele and are often masked by the normal allele. Here we report the development of a sensitive and specific diagnostic strategy based on somatic cell hybridization termed MAMA (monoallelic mutation analysis). We have demonstrated the utility of this strategy in two different hereditary colorectal cancer syndromes, one caused by a defective tumour suppressor gene on chromosome 5 (familial adenomatous polyposis, FAP) and the other caused by a defective mismatch repair gene on chromosome 2 (hereditary non-polyposis colorectal cancer, HNPCC).

Alleles↗
PubMed1997

Strategy for mutation detection in CLN3: characterisation of two Finnish mutations.

A strategy for detection of mutations in CLN3, the gene for Batten disease or juvenile onset neuronal ceroid lipofuscinosis, has been devised using a technique which detects conformation polymorphisms and direct sequencing of genomic DNA fragments. We define two mutations found uniquely in Finnish patients, one a large deletion (2.8 kb), the other a point mutation affecting the 5'splice donor site of an intron.

Adolescent↗
PubMed2004

Linkage of interactions in sickle hemoglobin fiber assembly: inhibitory effect emanating from mutations in the AB region of the alpha-chain is annulled by a mutation at its EF corner.

The AB and GH regions of the alpha-chain are located in spatial proximity and contain a cluster of intermolecular contact residues of the sickle hemoglobin (HbS) fiber. We have examined the role of dynamics of AB/GH region on HbS polymerization through simultaneous replacement of non-contact Ala(19) and Ala(21) of the AB corner with more flexible Gly or rigid alpha-aminoisobutyric acid (Aib) residues. The polymerization behavior of HbS with Aib substitutions was similar to the native HbS. In contrast, Gly substitutions inhibited HbS polymerization. Molecular dynamics simulation studies of alpha-chains indicated that coordinated motion of AB and GH region residues present in native (Ala) as well as in Aib mutant was disrupted in the Gly mutant. The inhibitory effect due to Gly substitutions was further explored in triple mutants that included mutation of an inter-doublestrand contact (alphaAsn(78) --> His or Gln) at the EF corner. Although the inhibitory effect of Gly substitutions in the triple mutant was unaffected in the presence of alphaGln(78), His at this site almost abrogated its inhibitory potential. The polymerization studies of point mutants (alphaGln(78) --> His) indicated that the inhibitory effect due to Gly substitutions in the triple mutant was synergistically compensated for by the polymerization-enhancing activity of His(78). Similar synergistic coupling, between alphaHis(78) and an intra-double-strand contact point (alpha16) mutation located in the AB region, was also observed. Thus, two conclusions are made: (i) Gly mutations at the AB corner inhibit HbS polymerization by perturbing the dynamics of the AB/GH region, and (ii) perturbations of AB region (through changes in dynamics of the AB/GH region or abolition of a specific fiber contact site) that influence HbS polymerization do so in concert with alpha78 site at the EF corner. The overall results provide insights about the interaction-linkage between distant regions of the HbS tetramer in fiber assembly.

Bacterial Proteins↗
PubMed1997

De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families.

Alleles↗
PubMed2000

Biallelic discrimination assays for the three common Ashkenazi Jewish mutations and a common non-Jewish mutation, in Tay-Sachs disease, using fluorogenic TaqMan probes.

We have developed rapid semiautomated fluorogenic TaqMan assays for the three common Jewish mutations that occur in Tay-Sachs disease, the TATC 4-bp insertion in exon 11 (1,278insTATC), the IVS 12 + 1G --> C, splice site mutation in intron 12 (1421 + 1 G --> C), and the G --> A change at the 3' end of exon 7 (G269S), as well as for a non-Jewish mutation, IVS9 + I G --> A, believed to be prevalent in patients of Celtic descent. The TaqMan assays are designed to run on the ABI SDS 7700 sequence detection system, using allele-specific probes that carry a reporter dye at the 5' end and a quencher dye at the 3' end. Using a 96-well format, all four assays can be performed simultaneously on the same plate, with real-time fluorescence detection or just an end-point plate read. DNA samples from 78 patients identified as carriers by biochemical screening and genotyped by conventional techniques were used to assess the accuracy and efficiency of the probes in allelic discrimination assays. There were no discrepancies noted between previously assigned genotypes and the results obtained by application of this methodology.

Alleles↗
PubMed1998

Mutations in ccf, a novel Drosophila gene encoding a chromosomal factor, affect progression through mitosis and interact with Pc-G mutations.

We report herein the isolation of ccf, a new gene located in region 82E and essential for Drosophila development. This gene, expressed throughout development, encodes a novel product of 68 kDa which is found in the nucleus during interphase and labels, in a novel pattern, centrosomes and chromosome arms during mitosis. Mutations in ccf give rise to late larvae with small imaginal discs and to adults showing appendages of reduced size, consistent with CCF involvement in cell proliferation. Neuroblast squash analyses show that CCF is required for proper condensation of mitotic chromosomes and, therefore, for progression through mitosis. Furthermore, we observe that adult ccf mutants as well as animals overexpressing CCF during larval stages exhibit homeotic transformations. We also find that mutations in the Pc-G genes Polycomb, polyhomeotic and Enhancer of zeste are enhanced by ccf mutations. Finally, we show that the CCF protein binds to specific sites on polytene chromosomes, many of which are shared with the Posterior sex combs Pc-G protein. Together, these results suggest a role for the CCF protein in the maintenance of chromosome structure during mitosis and interphase.

Amino Acid Sequence↗
PubMed2005

Of four mutations in the factor VII gene in Tunisian patients, one novel mutation (Ser339Phe) in three unrelated families abrogates factor X activation.

Hereditary factor VII (FVII) deficiency is a rare bleeding disorder. Dysfunctional FVII variants characterized by normal or reduced levels of FVII antigen and discordantly low FVII activity have been described. In this study, seven unrelated Tunisian patients with FVII deficiency were examined. Molecular analysis revealed that three probands harbored a novel Ser339Phe mutation, one proband was inferred to have a novel splice site mutation in intron 2, c.226-2 A>G and three probands had two previously described mutations, Arg304Gln and Cys310Phe. Expression of Ser339Phe in baby hamster kidney cells yielded secretion of FVII antigen at a concentration of 225+/-50 ng/ml, compared with 181+/-47 ng/ml in cells transfected with wild-type FVII but with no demonstrable FVII activity. FVII Ser339Phe bound to tissue factor similarly to the binding of commercial recombinant activated FVII or recombinant wild-type FVII and was normally activated by activated factor X. The major defect of FVII Ser339Phe was its inability to activate factor X in the presence of tissue factor. Modeling predicted that the substitution of Ser339 by Phe abrogated substrate docking.

DNA Mutational Analysis↗
PubMed1991

Haemophilia B mutations in a complete Swedish population sample: a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity.

Carrier and prenatal diagnosis based on the identification of the gene defect (direct diagnosis) increases the proportion of haemophilia B families that can be offered precise genetic counselling from the 50-60% attainable by DNA markers, to 100% and they also provide information on the molecular biology of the disease. We propose that in order to maximize the practical and scientific benefits of direct diagnosis the gene defect of complete (possibly national) populations of patients should be characterized and the information stored in appropriate confidential databases. We demonstrate the feasibility of such a strategy by characterizing the mutations of all the patients registered with the Malmö haemophilia centre. These patients (44 male and 1 female) are from 45 unrelated families and 24 (53%) have negative family history. The 25 patients with similar reduction of factor IX:C and factor IX:Ag (24 male + 1 female) have: two gross deletions, three frameshifts, four translation stops, six mutations expected to affect pre-mRNA splicing and 10 amino acid substitutions. The six patients with greater reduction of factor IX:C than factor IX:Ag and the seven with reduced IX:C and normal IX:Ag have only amino acid substitutions. Patients with inhibitors have: one complete deletion, one frameshift and three translation stops. One patient has both a translation stop and a functionally neutral amino acid substitution (His257----Tyr). Characterization of the factor IX mutation was successful in every case, usually entailed 4 person-days work, and has led to the identification of 12 amino acid residues essential for the factor IX structure and function.

Base Sequence↗
PubMed1993

Absence of cystic fibrosis mutations in a large Asian population sample and occurrence of a homozygous S549N mutation in an inbred Pakistani family.

The occurrence of cystic fibrosis is very rare in the Asian population. Carriers of the mutations most commonly found in Caucasians were not detected in a large Asian population sample of almost 900 chromosomes. However, an affected Pakistani child born to consanguineous parents was further investigated and shown to be homozygous for the mutation S549N (G-->A). Molecular and clinical data are presented which may improve our understanding of the phenotypic effects of the S549N mutation in the CFTR gene.

Asia↗
PubMed2002

A naturally occurring Tyr143His alpha IIb mutation abolishes alpha IIb beta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects.

The molecular basis for the interaction between a prototypic non-I-domain integrin, alpha(IIb)beta(3), and its ligands remains to be determined. In this study, we have characterized a novel missense mutation (Tyr143His) in alpha(IIb) associated with a variant of Glanzmann thrombasthenia. Osaka-12 platelets expressed a substantial amount of alpha(IIb)beta(3) (36%-41% of control) but failed to bind soluble ligands, including a high-affinity alpha(IIb)beta(3)-specific peptidomimetic antagonist. Sequence analysis revealed that Osaka-12 is a compound heterozygote for a single (521)T>C substitution leading to a Tyr143His substitution in alpha(IIb) and for the null expression of alpha(IIb) mRNA from the maternal allele. Given that Tyr143 is located in the W3 4-1 loop of the beta-propeller domain of alpha(IIb), we examined the effects of Tyr143His or Tyr143Ala substitution on the expression and function of alpha(IIb)beta(3) and compared them with KO (Arg-Thr insertion between 160 and 161 residues of alpha(IIb)) and with the Asp163Ala mutation located in the same loop by using 293 cells. Each of them abolished the binding function of alpha(IIb)beta(3) for soluble ligands without disturbing alpha(IIb)beta(3) expression. Because immobilized fibrinogen and fibrin are higher affinity/avidity ligands for alpha(IIb)beta(3), we performed cell adhesion and clot retraction assays. In sharp contrast to KO mutation and Asp163Ala alpha(IIb)beta(3), Tyr143His alpha(IIb)beta(3)-expressing cells still had some ability for cell adhesion and clot retraction. Thus, the functional defect induced by Tyr143His alpha(IIb) is likely caused by its allosteric effect rather than by a defect in the ligand-binding site itself. These detailed structure-function analyses provide better understanding of the ligand-binding sites in integrins.

Adult↗
PubMed1998

A novel splice site mutation of the EXT2 gene in a Finnish hereditary multiple exostoses family. Mutations in brief no. 197. Online.

Hereditary multiple exostoses is a dominantly inherited disease characterized by multiple benign osteochondromas. The affected individuals have an increased risk of developing sarcoma. A large Finnish family with hereditary multiple exostosis was analyzed to find the disease-causing mutation. Blood samples were obtained from 35 family members, including 21 affected and 14 unaffected individuals. Using 2-point linkage analysis the EXT phenotype was shown to be linked to the recently cloned EXT2 gene on chromosome 11p11. The coding region of the gene was sequenced and a previously unreported splice site mutation found. This G to T transversion within a 5-prime splice donor site following exon 6 was shown to cause aberrant splicing of RNA. The described change is considered to be a novel disease-causing mutation in the EXT2 gene.

Alternative Splicing↗
PubMed1999

Glycogen storage disease type Ia: four novel mutations (175delGG, R170X, G266V and V338F) identified. Mutations in brief no. 220. Online.

Deficient activity of glucose-6-phosphatase (G6Pase) causes glycogen storage disease type Ia (GSD Ia). We analysed the G6Pase gene of 16 GSD Ia patients using single strand conformation polymorphism (SSCP) analysis prior to automated sequencing of exon(s) revealing an aberrant SSCP pattern. In all GSD Ia patients we were able to identify mutations on both alleles of the G6Pase gene, indicating that this method is a reliable procedure to identify mutations. Four novel mutations (175delGG, R170X, G266V and V338F) were identified.

Amino Acid Substitution↗
PubMed1999

Identification of three novel mutations (Q54P, W70X and T108I) in the glucose-6-phosphatase gene of patients with glycogen storage disease type Ia. Mutation in brief no. 256. Online.

Three novel mutations, Q54P, W70X and T1081, were identified in the gene encoding glucose-6-phosphatase in three patients with glycogen storage disease type Ia. Two sibs of Portuguese origin were homozygous for the Q54P mutation whereas the third patient, originating from both France and Lebanon, was a compound heterozygote for the W70X and T108I mutations. Glycogen storage disease type Ia is a heterogeneous autosomal recessive condition.

Glucose-6-Phosphatase↗
PubMed1996

Mutagenic response to benzene and tris(2,3-dibromopropyl)-phosphate in the lambda lacI transgenic mouse mutation assay: a standardized approach to in vivo mutation analysis.

The genotoxic response of benzene and tris(2,3-dibromopropyl)-phosphate (TDBP) have been evaluated in several tissues using the standardized lambda/lacI (Big Blue) transgenic mouse mutation assay. Separate groups of four to five male B6C3F1 transgenic lambda/lacI mice were given oral administrations of benzene or TDBP at varying concentrations. Tissues evaluated include lung, bone marrow, and spleen in benzene-treated animals, and liver, kidney, and stomach in TDBP-treated animals. Significant increases in lacI mutations were observed in the spleen and bone marrow of benzene treated mice, and the kidneys of TDBP-treated mice. Where applicable, mutagenesis patterns of tissue sensitivity were consistent with what has been observed previously in other assays. In addition, mutagenicity in tissues not traditionally evaluated for mutations correlated to sites of carcinogenicity for the chemicals tested.

Animals↗
PubMed2004

Pendred syndrome and DFNB4-mutation screening of SLC26A4 by denaturing high-performance liquid chromatography and the identification of eleven novel mutations.

Mutations in SLC26A4 cause Pendred syndrome, an autosomal-recessive disorder characterized by sensorineural deafness and goiter, and DFNB4, a type of autosomal recessive nonsyndromic deafness in which, by definition, affected persons do not have thyromegaly. The clinical diagnosis of these two conditions is difficult, making mutation screening of SLC26A4 a valuable test. Although screening can be accomplished in a variety of ways, all techniques are not equally accurate, timely or cost effective. We found single-strand conformational polymorphism analysis (SSCP) to be 63% effective in detecting mutations a panel of different SLC26A4 allele variants when compared to data from direct sequencing. Because direct sequencing can be time consuming and expensive, especially for a gene with 21 exons, we studied DHPLC as an alternative screening method. We found DHPLC as accurate and reliable as direct sequencing but to be more rapid and cost effective. In addition, we report 11 novel disease-causing allele variants of SLC26A4.

Biological Transport↗
PubMed1982

Phenotypic reversion of an IS1-mediated deletion mutation: a combined role for point mutations and deletions in transposon evolution.

We have physically characterised a deletion mutant of the R plasmid R100 which has lost all of the antibiotic resistances, including chloramphenicol resistance (Cmr), coded by its IS1-flanked r-determinant. The deletion was mediated by one of the flanking IS1 elements and terminates within the carboxyl terminus of the Cmr gene. DNA sequence analysis showed that the mutated gene would produce a protein 20 amino acids longer than the wild-type due to fusion with an open reading frame in the IS element. Surprisingly for a deletion mutation, rare, spontaneous Cmr revertants could be recovered. Two of the four revertants studied had frame shifts due to the insertion of a single AT base pair at the same position; the revertants would code for a protein five amino acids shorter than the wild-type. The other two revertants had acquired duplications of the 34-bp inverted terminal repeat sequences of the IS1 element and would direct the synthesis of a protein six amino acids longer than the wild-type. The reverted Cmr markers were still capable of transposition. These observations suggest a role for point mutations and small DNA rearrangements in the formation of new gene organisations produced by mobile genetic elements.

Base Sequence↗
PubMed1991

Mutation pattern of immunoglobulin transgenes is compatible with a model of somatic hypermutation in which targeting of the mutator is linked to the direction of DNA replication.

We have previously demonstrated that B lymphocyte specific somatic mutations are introduced into the variable regions of immunoglobulin kappa transgenes in two independent transgenic mouse lines. The frequency, distribution and nature of these mutations strongly suggest that they arose as a result of the process of somatic hypermutation, which is responsible, in part, for affinity maturation during an immune response. Unexpectedly, in these multiple copy transgenic lines, many of the transgene copies showed no evidence of somatic mutation. This paradox was addressed by determining the sequence of each transgene copy in several B cell hybridomas derived from a mouse line carrying three copies of the kappa transgene. It was found that the somatic hypermutation process in different B cells from the same mouse preferentially targets one, but not the same, transgene copy. We present a model, based on the pattern of this targeting, which links somatic hypermutation to the orientation of the Ig gene relative to the direction of DNA replication.

Animals↗
PubMed1994

The Yaa mutation induces the development of autoimmunity in mice heterozygous for the gld (generalized lymphadenopathy disease) mutation.

Mice homozygous for either the generalized lymphoproliferative disease (gld) or the lymphoproliferation (lpr) nonallelic mutations develop similar syndromes combining systemic autoimmunity and lymphoproliferative disease. Though essentially recessive, the lpr and gld mutations may be expressed in the heterozygous state: [lpr/+] mice displayed a mild "lpr-like" autoimmunity, and the [lprcg/+ gld/+] mice developed a "gld-like" disorder, showing interactions of the gld gene product with the nonallelic lprcg product. The Y-chromosome-linked autoimmune accelerator (Yaa) mutation being an autoimmunity accelerator, its association with an heterozygous gld gene might also bring a gld-like syndrome. The [gld/+ Yaa] mice were shown here to develop autoimmunity and splenomegaly like [gld/gld] mice, but without their typical lymphadenopathy. Furthermore, the [gld/+ Yaa] splenomegaly was not due to the expansion of the unusual Thy1+ B220+ T-cell subset typical of the gld syndrome, but rather to a polyclonal expansion of the major lymphoid cell subsets. Thus, the syndrome shown by [gld/+ Yaa] mice was not a gld-like syndrome. This suggests that the interactions of the gld gene product with the Yaa product and with the lprcg product must be different.

Animals↗