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R I Richards

Publications and source records attributed to R I Richards.

At least 37 records · Page 2Linked to original sources
PubMed1997

Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene.

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were described at first in the heritable connective tissue disorder, Marfan syndrome (MFS). More recently, FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally non-recurrent and widely distributed throughout the gene. To date no clear genotype/phenotype relationship has been observed excepted for the localization of neonatal mutations in a cluster between exons 24 and 32. The second version of the computerized Marfan database contains 89 entries. The software has been modified to accomodate new functions and routines.

Animals↗
PubMed1997

Dynamic mutation: possible mechanisms and significance in human disease.

Increases in repeat-DNA copy number are the molecular basis of a growing list of human genetic diseases, including fragile X syndrome, myotonic dystrophy, Huntington disease and a form of epilepsy. Repeat-DNA sequences undergo a unique process of dynamic mutation, the common properties of which probably reflect common molecular events. This form of mutation is no longer restricted to trinucleotide repeats, because repeats of different length have been found to undergo expansion.

Genetic Diseases, Inborn↗
PubMed1997

Genetic heterogeneity in familial acute myelogenous leukemia: evidence for a second locus at chromosome 16q21-23.2.

The identification of genes responsible for the rare cases of familial leukemia may afford insight into the mechanism underlying the more common sporadic occurrences. Here we test a single family with 11 relevant meioses transmitting autosomal dominant acute myelogenous leukemia (AML) and myelodysplasia for linkage to three potential candidate loci. In a different family with inherited AML, linkage to chromosome 21q22.1-22.2 was recently reported; we exclude linkage to 21q22.1-22.2, demonstrating that familial AML is a heterogeneous disease. After reviewing familial leukemia and observing anticipation in the form of a declining age of onset with each generation, we had proposed 9p21-22 and 16q22 as additional candidate loci. Whereas linkage to 9p21-22 can be excluded, the finding of a maximum two-point LOD score of 2.82 with the microsatellite marker D16S522 at a recombination fraction theta = 0 provides evidence supporting linkage to 16q22. Haplotype analysis reveals a 23.5-cM (17.9-Mb) commonly inherited region among all affected family members extending from D16S451 to D16S289. In order to extract maximum linkage information with missing individuals, incomplete informativeness with individual markers in this interval, and possible deviance from strict autosomal dominant inheritance, we performed nonparametric linkage analysis (NPL) and found a maximum NPL statistic corresponding to a P-value of .00098, close to the maximum conditional probability of linkage expected for a pedigree with this structure. Mutational analysis in this region specifically excludes expansion of the AT-rich minisatellite repeat FRA16B fragile site and the CAG trinucleotide repeat in the E2F-4 transcription factor. The "repeat expansion detection" method, capable of detecting dynamic mutation associated with anticipation, more generally excludes large CAG repeat expansion as a cause of leukemia in this family.

Chromosome Mapping↗
PubMed1997

Localisation of a 10q breakpoint within the PAX2 gene in a patient with a de novo t(10;13) translocation and optic nerve coloboma-renal disease.

We describe a 5 year old boy with a de novo t(10;13) translocation and optic nerve coloboma-renal disease (ONCR). On the basis of GTG banding analysis of prometaphase chromosomes, the patient's karyotype was interpreted as either 46,XY,t(10;13)(q24.3;q12.3) or t(10;13) (q25.2;q14.1). Fluorescence in situ hybridisation (FISH) studies using a YAC clone containing the PAX2 gene and YAC clones adjoining FRA10B at 10q25.2 showed that the 10q breakpoint had occurred just within the PAX2 gene and was proximal to FRA10B. These FISH results suggest that the translocation causes a disruption of the PAX2 gene and leads to ONCR, in agreement with the recent reports of PAX2 mutations in two unrelated families with ONCR. Furthermore, we refined the regional mapping of the human PAX2 gene to the junction of bands 10q24.3 and 10q25.1.

Child, Preschool↗
PubMed1996

Unusual inheritance patterns due to dynamic mutation in fragile X syndrome.

Fragile X syndrome is the most common form of familial mental retardation and is one of the world's most common genetic diseases. The inheritance patterns of the disease have many unusual features. It is an X-linked disorder yet there are asymptomatic carrier males. The disease is expressed only when the gene is inherited from the mother. The risk of a carrier woman having a child with the syndrome depends upon her position in the pedigree (the Sherman paradox) and her own intellectual status. The discovery that the disease is due to dynamic mutation (which is a multistage process) that inactivates FMR1 has provided an explanation for the unusual inheritance patterns. The finding of linkage disequilibrium between the fragile X mutations and closely linked DNA markers (haplotype) has required a reinterpretation of this phenomenon for dynamic mutations. Only a small number of normal alleles at the fragile X locus have long stretches of perfect repeat (2% with more than 24 copies) and these form a reservoir of alleles that can increase in length into the premutation range. Dynamic mutation is, so far, an exclusively human phenomenon, but this is probably because it has yet to be discovered in other species. Unusual inheritance patterns are a hallmark of dynamic mutation diseases.

Alleles↗
PubMed1996

Dynamic mutation loci: allele distributions in different populations.

To assess the relative contributions of trans-acting factors (replication and repair functions) and cis-acting elements (repeat and flanking DNA composition) to the mechanism of trinucleotide repeat sequence mutation we have analysed the distribution of copy number polymorphisms at 12 loci associated with dynamic mutations in 15 populations of different ethnic origins. Genome wide instability of repeats in a particular population would be evidence of trans-acting factor instigation of the mutation process, whereas instability at a particular locus (perhaps even in several populations) would be evidence that the composition of the particular locus was the most significant factor contributing to mutation. The FRA16A locus is highly polymorphic in only the European population. Some other loci exhibit distinct distributions of alleles between different populations. Therefore sequences in the vicinity of the repeat -- the cis component of a particular locus -- appear(s) to be more important in the mutation mechanism than sporadic genome-wide instability induced by trans-acting factors such as the DNA mismatch repair enzymes.

Alleles↗
PubMed1996

Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246.

This report presents refined genetic mapping data for the gene causing familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation. We sampled 65 Jewish, Armenian, and Arab families and typed them for eight markers from chromosome 16p. Using a new algorithm that permits multipoint calculations for a dense map of markers in consanguineous families, we obtained a maximal LOD score of 49.2 at a location 1.6 cM centromeric to D16S246. A specific haplotype at D16S283-D16S94-D16S246 was found in 76% of Moroccan and 32% of non-Moroccan Jewish carrier chromosomes, but this haplotype was not overrepresented in Armenian or Arab FMF carriers. Moreover, the 2.5-kb allele at D16S246 was significantly associated with FMF in Moroccan and non-Moroccan Jews but not in Armenians or Arabs. Since the Moroccan Jewish community represents a relatively recently established and genetically isolated founder population, we analyzed the Moroccan linkage-disequilibrium data by using Luria-Delbrück formulas and simulations based on a Poisson branching process. These methods place the FMF susceptibility gene within 0.305 cM of D16S246 (2-LOD-unit range 0.02-0.64 cM).

Algorithms↗
PubMed1995

Association of a chromosome deletion syndrome with a fragile site within the proto-oncogene CBL2.

The fragile site FRA11B has been localized to the p(CCG)n repeat of the CBL2 proto-oncogene. A proportion of Jacobsen (11q-) syndrome patients inherited a chromosome carrying a CBL2 p(CCG)n expansion, which was truncated close to FRA11B. These results have broad implications for the role of p(CCG)n repeat expansion in the aetiology of genetic disease involving chromosome rearrangements.

Base Sequence↗
PubMed1995

Simple tandem DNA repeats and human genetic disease.

The human genome contains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an increase in copy number by a process of dynamic mutation. Dynamic mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromosomes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most common familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of mental retardation. Similar mutations of AGC repeats give rise to a number of neurological disorders. The expanded repeats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance--particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of dynamic mutation is discussed, and a number of observations of simple tandem repeat mutation that could assist in understanding this phenomenon are commented on.

Chromosome Mapping↗
PubMed1995

The molecular basis of fragile sites in human chromosomes.

Fragile sites on chromosomes have been classified into a number of groups according to their frequency and the conditions required to induce them. A number of the rare folate-sensitive fragile sites have been characterized and shown to be amplified methylated CCG trinucleotide repeats. One common fragile site has been partly characterized and appears to be a region of fragility, rather than a single site.

Aphidicolin↗
PubMed1995

Molecular basis of p(CCG)n repeat instability at the FRA16A fragile site locus.

Rare, folate-sensitive fragile sites are the result of the unstable expansion of trinucleotide p(CCG)n repeats, which are normally polymorphic in copy number. Differences in the number and frequency of alleles of the fragile site FRA16A p(CCG)n repeat were observed between different ethnic populations suggesting that certain alleles might be predisposed to instability. Sequence analysis demonstrated that the longer and more variable alleles were associated with loss of repeat interruption. Perfect repeat configuration therefore appears to be a necessary precondition for the instability associated with fragile site genesis.

Alleles↗
PubMed1994

Haplotype analysis at the FRAXA locus in the Japanese population.

Fragile X syndrome, one of the most common human genetic diseases, is characterized by a unique genetic mechanism which involves dynamic mutation in a heritable unstable DNA sequence, a p(CCG)n repeat, in the FRAXA locus. It has recently been suggested that a few founder chromosomes are responsible for most fragile X mutations in the Caucasian population. In order to investigate the origin of the fragile X mutations in the Japanese population, we analyzed haplotypes of the FRAXA locus in 40 unrelated fragile X chromosomes and 142 normal X chromosomes in Japanese males, by using two polymorphic AC repeats, FRAXAC1 and FRAXAC2, which flank the fragile site. This analysis provided evidence for founder fragile X chromosomes in the Japanese population, similar to that in Caucasians, although different haplotypes are involved. The distribution of normal allele size of the p(CCG)n repeat among the X chromosomes in the Japanese population is very similar to that reported for Caucasians, except that the most frequent copy number (n = 28) is one copy less than that in Caucasians and that there is an additional peak at 35 copies. There is significant correlation between FRAXAC alleles and the p(CCG)n repeat copy number in non-fragile X chromosomes, however, alleles with more than 31 copies of the p(CCG)n repeat do not segregate with either of the fragile X common FRAXAC haplotypes.

Asian People↗
PubMed1994

Implications of FRA16A structure for the mechanism of chromosomal fragile site genesis.

Fragile sites are chemically induced nonstaining gaps in chromosomes. Different fragile sites vary in frequency in the population and in the chemistry of their induction. DNA sequences encompassing and including the rare, autosomal, folate-sensitive fragile site, FRA16A, were isolated by positional cloning. The molecular basis of FRA16A was found to be expansion of a normally polymorphic p(CCG)n repeat. This repeat was adjacent to a CpG island that was methylated in fragile site-expressing individuals. The FRA16A locus in individuals who do not express the fragile site is not a site of DNA methylation (imprinting), which suggests that the methylation associated with fragile sites may be a consequence and not a cause of their genesis.

Alleles↗
PubMed1994

Isolation and characterization of transcribed sequences from a chromosome 16 hn-cDNA library and the physical mapping of genes and transcribed sequences using a high-resolution somatic cell panel of human chromosome 16.

A hn-cDNA (heteronuclear complementary DNA) library was constructed from a mouse/human somatic cell hybrid, CY18, which contains chromosome 16 as the only human chromosome. Hexamer primers constructed from consensus 5' intron splice sequences were used to generate cDNA from the immature unspliced mRNA. The resulting cDNA library was screened with a total human DNA probe to identify potential human clones. Rescreening was necessary, and use of a mouse-derived clone with homology to 7SL RNA proved successful in eliminating the majority of mouse clones. Thirteen clones had open reading frames, and of those, five showed homology to human sequences in GenBank. Two clones had homology to random partially sequenced cDNAs, one clone was likely to be a GRP78 pseudogene, one clone mapped the PHKG2 gene to 16p11.2-16p12.1, and one clone had homology to human S13 ribosomal protein. All clones except the latter were mapped to a high-resolution somatic cell panel. Although isolation of human chromosome 16 genes from this library was successful, it was apparent that cDNA synthesis was initiated at sites other than intron splice sites, presumably by mispairing of the hexamers.

Animals↗