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PubMed1996

A fragile X male with a broad smear on Southern blot analysis representing 100-500 CGG repeats and no methylation at the EagI site of the FMR-1 gene.

Fragile X DNA studies were carried out on all obligate carriers of a large fragile X family with 10 mentally retarded individuals. One 64-year-old carrier man with an altered FMR-1 allele was not described as being mentally retarded or as having any limitations in function. He was married, raised 8 children, and worked as an auto mechanic. On examination, he had macrocephaly and mild macroorchidism but few of the other typical physical findings of males with fragile X syndrome. His Full Scale IQ is 73, and his Vineland Adaptive Behavior Composite is 73. On the Woodcock-Johnson Psycho-Educational Battery-Revised, he achieved standard scores of 64 in Reading, 55 in Math, and 83 in Knowledge. His DNA findings showed a broad smear on Southern blot analysis of 100-500 CGG repeats and no methylation at the EagI site upstream of the FMR-1 protein coding region. His FMR-1 protein production is 12% of normal. His daughters all have large premutations, with somatic instability in the size of the CGG repeat lengths. They all have evidence of academic underachievement and 2 have physical characteristics frequently described in individuals with fragile X.

Blotting, Southern↗
PubMedDate not supplied

Analysis of mutations at the fragile X locus using the DNA probe Ox1.9.

In this study, 40 families segregating for fragile X [fra (X)] syndrome were examined for the presence of a mutation within the FMR-1 gene. Using the DNA probe Ox1.9, both carriers and affected individuals were found to contain an insertion/amplification-type of mutation with somatic instability. Variability in the size of the mutation, which ranged from less than 0.2 kb to approximately 13 kb, was observed both between individuals (even from the same family) and within individuals, who showed a smear rather than a discrete band(s) on Southern blot analysis. Transmission of the mutation by males resulted in little change of its size, while transmission by females usually resulted in an increase in size. Correlations were observed between the size of inserted/amplified DNA and the level of chromosome fragility and the presence or absence of mental impairment. Overall, a mutation was detected in 66 of 67 (99%) clinically affected males, in 12 of 13 (92%) transmitting males and in 95 of 112 (85%) carrier females. Equivocal results were obtained in 12 (11%) of the carrier females. No mutation was detected in 58 females and 33 males predicted to be normal by linkage, or in one female and 36 normal control males. These results strongly suggest that the mutation detected by Ox1.9 is closely associated with the cytogenetic and clinical expression of fra (X) syndrome. Additionally, the use of this probe along with other probe/enzyme combinations should provide a sensitive clinical assay for the detection of carriers of fra (X) syndrome.

Cytogenetics↗
PubMed2004

Friedreich ataxia in carriers of unstable borderline GAA triplet-repeat alleles.

Friedreich ataxia patients are homozygous for expanded GAA triplet-repeats containing 66 to 1,700 triplets. We report two patients with delayed-onset, hyperreflexia and gradually progressive disease. Both were heterozygous for large expansions and also carried alleles with 44 and 66 triplet-repeats, respectively. Due to somatic instability, 15% (GAA-44) and 75% (GAA-66) of cells contained alleles with >/=66 triplet-repeats, constituting a plausible mechanism for their mild phenotype. A sibling with a stable GAA-37 allele and a large expansion was clinically normal. Instability of borderline alleles confers a risk for Friedreich ataxia, and the range of pathogenic alleles is broader than previously recognized.

Alleles↗
PubMed2004

Association of spinal and bulbar muscular atrophy with myotonic dystrophy type 1.

A man with spinal and bulbar muscular atrophy (SBMA) had a short (CTG)n expansion in the myotonic dystrophy protein kinase gene as well as (CAG)n expansion in the androgen receptor gene in leukocytes. The patient had the characteristic clinical findings of SBMA, but none of myotonic dystrophy type 1 (DM1). All of his three children (a son and two daughters) had the DM1 phenotype with long (CTG)n expansions. The daughters also had heterozygous long (CAG)n expansions. Postmortem examination of the patient revealed the characteristic pathological changes of SBMA as well as muscle degeneration compatible with DM1. Gene analysis of the organs disclosed unstable long expansions of the (CTG)n repeats, in contrast to the stable (CAG)n expansions. We have assumed that SBMA and DM1 developed independently in our patient, but cannot exclude the possibility that interactive gene effects increased somatic instability.

Adult↗
PubMed1994

The MLLT3 gene maps between D9S156 and D9S171 and contains an unstable polymorphic trinucleotide repeat.

MLLT3, one of the genes shown to be a translocation breakpoint partner for the acute lymphocytic leukemia (MLL) gene, has been mapped to 9p22. We have identified a polymorphic trinucleotide repeat within this gene that shows somatic instability. The inheritance pattern of this polymorphism in recombinant individuals from families previously typed for other chromosome 9 markers indicates that the gene lies in the interval bounded by D9S156 and D9S171.

Alleles↗
PubMed1988

Regulation of mutator activities in maize.

We discuss the properties of the Mutator (Mu) transposable element family of maize. We report the cloning of bz2-mu1, a mutable allele containing a 1.4-kb Mu element, using a combination of transposon tagging and tests for differential hybridization to northern and Southern blots. We report the sequence of this allele and the Mu element insertion, and propose a model for the structure of the Bz2 locus. We discuss the relationship between increased DNA modification of Mu elements and loss of somatic instability at bz2-mu1. To further explore this aspect of regulation of Mutator, we have used gene-specific probes to determine the level of modification at this locus in active and inactive Mutator lines. We have also utilized CsCl density gradients to estimate the overall level of DNA modification in active and inactive lines; we find that Mu elements in active lines are hypomethylated relative to other maize nuclear DNAs examined, and that in inactive lines the level of modification in Mu elements is similar to the genome as a whole. Utilizing gamma-irradiation, we have demonstrated that inactive lines can be reactivated; this reactivation is first noted as restitution of the spotted kernel phenotype characteristic of bz2-mu1 in active Mutator lines. Hybridization analysis of DNA from reactivated plants demonstrates that the Mu elements in general, and specifically the Mu element at bz2-mu1, have the lower level of DNA modification characteristic of active lines. These results are discussed in terms of the role and timing of DNA modification in regulating Mutator activities.

Base Sequence↗
PubMed1992

Reactivation of Mutator transposable elements of maize by ultraviolet light.

After epigenetic loss of Mutator activity, the family of Mu elements in Zea mays becomes immobile and highly methylated; in addition, Mu9, the presumptive autonomous regulatory element, is transcriptionally silent and its copy number decreases in successive crosses to non-Mutator lines. Spontaneous reactivation, scored as restoration of somatic instability of potentially mutable alleles of Bronze-2, of such cryptic Mutator lines is rare, occurring with a frequency of about 10(-4). Irradiation of pollen with 254 nm ultraviolet light increases reactivation rate in the progeny kernels by up to 40-fold. Accompanying reactivation, the copy number of Mu9 elements increased, two-fold in one line and 20 to 40-fold in a second line. Reactivation may involve direct DNA damage or immediate physiological stress in the treated pollen.

DNA↗
PubMed1995

Somatic cell heterogeneity between DNA extracted from lymphocytes and skeletal muscle in congenital myotonic dystrophy.

Myotonic dystrophy (DM) results from the expansion of an unstable CTG trinucleotide repeat in the 3' untranslated region of mRNA encoding a putative serine/threonine protein kinase. The degree of the CTG repeat amplification in genomic DNAs extracted from lymphocytes correlates with disease severity. We have analyzed the amplification of the CTG repeat of DNAs extracted from skeletal muscles and lymphocytes in five congenital DM patients. The amplification from skeletal muscles showed an increase of about 1.5 kb to 3.5 kb larger than that from lymphocytes in all patients. Furthermore, we have investigated the somatic instability of the CTG repeat in various tissues from a severe congenital DM patient.

Adolescent↗
PubMed2003

The HY2 gene as an efficient marker for transposon excision in Arabidopsis.

Transposable elements can generate germinal and somatic mutations, and hence represent a powerful tool for the analysis of gene function. Transposons from maize have been adapted to mutagenise the genomes of diverse species. The efficiency of these systems partly relies on the ease with which germinal (i.e. germinally transmitted) or somatic excisions can be detected. Here we describe the use of HY2, a gene that codes for an enzyme involved in the biosynthesis of the phytochrome chromophore, to monitor the excision of a Ds gene-trap element in Arabidopsis thaliana. Taking advantage of the altered germination and de-etiolation behaviour of a Ds -tagged hy2 mutant, we have designed an efficient protocol for the recovery of germinal revertants, making HY2 the most precocious excision marker available, to the best of our knowledge. In addition, HY2 is also useful for generating visible sectors in photosynthetic tissues, thanks to the somatic instability of this mutable hy2 allele.

Arabidopsis↗
PubMed2004

Characterization of a single nucleotide polymorphism in the ZNF9 gene and analysis of association with myotonic dystrophy type II (DM2) in the Italian population.

Myotonic dystrophy type 2 (DM2) is a dominant inherited disorder clinically similar to myotonic dystrophy type 1 (DM1) with a peculiar pattern of multisystemic phenotypic features. The mutation responsible for DM1 is a CTG repeat in the 3' UTR of the dystrophia myotonica protein kinase gene (DMPK) on chromosome 19q13.3, while DM2 is caused by an unstable CCTG expansion in intron 1 of the zinc finger protein 9 gene (ZNF9) on chromosome 3q21.3. Southern blotting analysis is the conventional test used to determinate the size of the repeats in the molecular diagnosis of DM2. However, the large number of CCTG repeats and their somatic instability complicates this diagnostic protocol. In order to improve the DM2 test, we have recently characterised a single nucleotide polymorphism located in the first intron of the ZNF9 gene. This SNP consists in a C to A nucleotide change, which creates or disrupts and ApaI enzyme restriction site, easily detectable by PCR amplification followed by restriction analysis. We genotyped this SNP in 30 unrelated DM2 patients and 70 unrelated Italians healthy individuals. Our results show that this polymorphism is in linkage disequilibrium with the DM2 mutation.

Case-Control Studies↗
PubMed1999

A genetic program for deletion of foreign DNA from the mammalian genome.

Mammalian genomes are in constant jeopardy of invasion by prokaryotic DNA sequences because of their extensive exposure to bacteria; however, mammalian genomes appear to be protected from horizontal transmission of bacterial DNA. Transgenic mice provide a convenient model system for investigating the capacity of mammalian genomes in vivo to retain, silence, and/or reject foreign DNAs. We have previously reported that bacterial genes encoding the Lac repressor (lacI) are subject to sequence-dependent methylation and silencing in the transgenic mouse. In this paper, we report that bacterially derived lacI transgenes, but not their mammalian counterparts, can also be eliminated from the somatic cell DNA of affected animals. This somatic instability is heritable, strain-dependent, and conferred in cis. Our data are consistent with a model of genome surveillance in the mouse which can lead to loss of foreign DNA and which may be analogous to restriction-modification systems that maintain the integrity of the bacterial genome.

Animals↗
PubMed1992

Molecular genetics of the fragile-X syndrome: a novel type of unstable mutation.

Fragile-X syndrome, the most common inherited form of mental retardation, has a very unusual mode of inheritance. The disease is caused by a multistep expansion, in successive generations, of a polymorphic CGG repeat localized in a 5' exon of FMR-1, a gene of unknown function. Two main mutation types have been categorized. Premutations are moderate expansions of the repeat and do not cause mental retardation. Full mutations are found in affected individuals and involve larger expansions of the repeat, with abnormal methylation of the neighboring CpG island. The full mutations demonstrate striking somatic instability and extinguish expression of FMR-1. Premutations are changed to full mutation only when transmitted by a female with a frequency that increases up to 100% as a function of the initial size of the premutation. Direct detection of the mutations provides an accurate test for pre- and postnatal diagnosis of the disease, and for carrier detection. A similar unstable expansion of a trinucleotide repeat occurs in myotonic dystrophy.

Cloning, Molecular↗
PubMed2026

Toward the clinical application of long-read sequencing in repeat-expansion disorders.

Repeat-expansion disorders (REDs) are a mechanistically and clinically well-defined subgroup of rare diseases caused by the expansion of short tandem repeats (STRs). These expansions can exceed several kilobases and show complex features, such as noncanonical secondary structures, somatic instability, repeat interruptions and allele-specific methylation. These characteristics are highly relevant for understanding disease mechanisms, clinical variability, prognosis and potentially therapeutic decision-making, but cannot be fully resolved using traditional diagnostic methods or short-read sequencing technologies. By contrast, long-read sequencing (LRS) enables accurate investigation of STR complexity in a single assay, facilitates the discovery of new pathogenic repeat expansions and drives advances in diagnostics, clinical and basic research, which may allow for better patient stratification in future clinical trials. This Perspective discusses recent LRS-driven discoveries, methodological and bioinformatic advances, and emerging diagnostic applications to illustrate the potential of LRS in reshaping both research and clinical practice.

Humans↗
PubMed2000

Extended structural variation of a pentanucleotide repeat in the GSTP1 gene: characterisation in a normal population and in thyroid and gastric tumours.

The promoter region of the human GSTP1 gene contains a polymorphic short tandem repeat (STR) locus consisting of pentanucleotide repeat units (ATAAA). In this work we report the existence of a total of 26 alleles in a Caucasian population. While differences in size (ranging from one to five base pairs) were responsible for the major variation, in five size-defined classes, two alternative sequences were found. Automatic fragment sizing and sequencing analysis revealed that this polymorphism is of a highly complex nature in contrast with previous reports. A genetic population study was carried out on a random sample from Portugal showing no deviation from Hardy-Weinberg equilibrium. Somatic instability studies were also performed on gastric and thyroid tumours using this STR: no instability was detected in thyroid tumour tissues when compared with their normal counterpart but in gastric tumour tissues microsatellite instability (MSI) was detected in 9.6% of the cases and loss of heterozygosity (LOH) also in 9.6% of the cases studied. The results obtained with GSTP1 in gastric cancer were compared with previously reported data on MSI using BAT-26 and several dinucleotide repeat markers.

Alleles↗
PubMed1987

Construction of an unstable Ring-X chromosome bearing the autosomal dopa decarboxylase gene in Drosophila melanogaster and analysis of Ddc mosaics.

An unstable Ring-X chromosome, Ddc+ -Ring-X carrying a cloned Dopa decarboxylase (Ddc) encoding segment was constructed. The construction involved a double recombination event between the unstable Ring-X, R(1)wvC and a Rod-X chromosome which contained a P-element mediated Ddc+ insert. The resulting Ddc+ -Ring-X chromosome behaves similarly to the parent chromosome with respect to somatic instability. The Ddc+ -Ring-X chromosome was used to generate Ddc mosaics. Analyses of Ddc mosaics revealed that while there was no absolute requirement for the Ddc+ expression in either the epidermis or the nervous system, very large mutant clones did affect the viability of the mosaic.

Animals↗
PubMed1995

Somatic mosaicism of CAG repeat in dentatorubral-pallidoluysian atrophy (DRPLA).

An unstable expansion of CAG repeat in the coding region of the DRPLA gene on chromosome 12p is the mutation specific for hereditary dentatorubral-pallidoluysian atrophy (DRPLA). We studied the CAG expansion in brain and other tissues from six unrelated DRPLA patients. The CAG repeat lengths showed distinct differences between tissues. The sizes of the CAG expansion in various regions of the brain except the cerebellum were generally larger by several repeats than in other peripheral tissues. Brain samples showed greater variation of the expansion compared with other tissues, but neither the size of the CAG expansion nor the degree of CAG repeat variation parallels the detailed findings of neuropathological involvement. We conclude that somatic instabilities of the CAG repeat cause tissue variability of the CAG repeat size in DRPLA but other region or cell type-specific factors would be involved to explain the selectivity of cell damage in DRPLA.

Adult↗
PubMed1995

Integrated control of seed maturation and germination programs by activator and repressor functions of Viviparous-1 of maize.

The Viviparous-1 (VP1) transcriptional activator of maize is required for abscisic acid induction of maturation-specific genes late in seed development leading to acquisition of desiccation tolerance and arrest in embryo growth. Here, we show that VP1 also inhibits induction of the germination-specific alpha-amylase genes in aleurone cells of the developing seed and thereby appears to be involved in preventing precocious hydrolyzation of storage compounds accumulating in the endosperm. In developing seeds of the somatically instable vp1-m2 mutant, hydrolase activity was derepressed specifically in endosperm sectors underlying vp1 mutant aleurone. A barley alpha-amylase promoter-GUS reporter construct (Amy-GUS) was induced in developing vp1 mutant aleurone cells but not in wild-type aleurone cells. Moreover, transient expression of recombinant VP1 and vp1 mutant aleurone cells strongly inhibited expression of Amy-GUS and thus effectively complemented this aspect of the mutant phenotype. VP1 specifically repressed induction of Amy-GUS by the hormone gibberellic acid in aleurone of germinating barley seeds. Deletion of the acidic transcriptional activation domain of VP1 did not affect the inhibitory activity, indicating that VP1 has a discrete repressor function. Hence, physically combining activator and repressor functions in one protein may provide a mechanism to integrate the control of two normally consecutive developmental programs, seed maturation and seed germination.

DNA-Binding Proteins↗
PubMed1995

Genetic counselling in complete androgen insensitivity syndrome: trinucleotide repeat polymorphisms, single-strand conformation polymorphism and direct detection of two novel mutations in the androgen receptor gene.

OBJECTIVE: Androgen insensitivity syndrome is a disorder of male sexual development which results in varying degrees of undervirilization in 46XY individuals with functional testes. In the most severe form, complete androgen insensitivity syndrome (CAIS), patients have a normal female appearance. Although CAIS is not life-threatening, affected individuals are infertile and require counselling, gonadectomy, hormone therapy, and sometimes vaginoplasty. Many families therefore request genetic counselling. Defects in the androgen receptor gene account for most if not all cases of CAIS. The purpose of this study was to evaluate the use of the polyglutamine and polyglycine trinucleotide repeat polymorphisms in the first exon of the androgen receptor gene for carrier status determination in three CAIS families. In two of these families novel mutations in the androgen receptor gene were subsequently identified which allowed confirmation of carrier status and also a prenatal diagnosis to be made in one family. PATIENTS: Three CAIS families were studied. The index cases all presented with a clinical phenotype typical of CAIS. MEASUREMENTS: Family members were typed initially for the polyglutamine repeat. In one family this was not informative and the polyglycine repeat was therefore studied. In this and one further family, the androgen receptor gene was sequenced to identify the mutation causing the CAIS. RESULTS: On the basis of information from trinucleotide repeat analysis carrier status could be assessed in each family. In one family, evidence for somatic instability of the polyglutamine repeat was found. In the same family, a novel mutation in the androgen receptor gene, which substituted valine for leucine 881, was identified. Other family members were subsequently typed for the mutation and a prenatal diagnosis was performed. A novel mutation was also identified in a second family substituting the glycine codon at position 371 with a stop codon. Other family members were typed for this mutation. CONCLUSIONS: Both the polyglutamine and polyglycine repeat polymorphisms are useful for the genetic counselling of complete androgen insensitivity syndrome families. In some cases, however, where the family history is limited, more precise information can be provided only once the androgen receptor mutation causing the complete androgen insensitivity syndrome has been identified.

Adolescent↗