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J C Mulley

Publications and source records attributed to J C Mulley.

At least 55 records · Page 3Linked to original sources
PubMed1996

Refinement of the background genetic map of Xq26-q27 and gene localisation for Börjeson-Forssman-Lehmann Syndrome.

A detailed map of genetic markers was constructed around the gene for the X-linked mental retardation syndrome of Börjeson-Forssman-Lehmann (BFLS). A multipoint linkage map of framework markers across Xq26-27, based on CEPH families, was integrated with the physical map, based on a YAC contig, to confirm marker order. The remaining genetic markers, which could not be ordered by linkage, were added to create the comprehensive genetic back-ground map, in the order determined by physical mapping, to determine genetic distances between adjacent markers. This background genetic map is applicable to the refinement of the regional localisation for any disease gene mapping to this region. The BFLS gene was localised using this background map in an extended version of the family described by Turner et al. [1989]. The regional localisation for BFLS extends between recombination events at DXS425 and DXS105, an interval of 24.6 cM on the background genetic map. The phenotypic findings commonly seen in the feet of affected males and obligate carrier females may represent a useful clinical indicator of carrier status in potential female carriers in the family. Recombination between DXS425 and DXS105 in a female with such characteristic feet suggests that the distal limit of the regional localisation for the BFLS gene might reasonably be reduced to DXS294 for the purpose of selecting candidate genes, reducing the interval for the BFLS gene to 15.5 cM. Positional candidate genes from the interval between DXS425 and DXS105 include the SOX3 gene, mapped between DXS51(52A) and DXS98(4D-8). SOX3 may have a role in regulating the development of the nervous system. The HMG-box region of this single exon gene was examined by PCR for a deletion and then sequenced. No deviation from normal was observed, excluding mutations in the conserved HMG-box region as the cause of BFLS in this family.

Chromosome Mapping↗
PubMed1996

Fragile X syndrome and fragile XE mental retardation.

There are two forms of mental handicap associated with fragile sites on the end of the long arm of the X chromosome. The well known common disorder Fragile X syndrome is associated with FRAXA and a rare non-specific form of mental handicap is associated with FRAXE. The cytogenetics of these fragile sites is considered. For Fragile X syndrome details are given of the molecular genetics, inheritance patterns, genetic counselling, methods for diagnosis of index cases, carrier detection and prenatal diagnosis. Series of prenatal diagnoses are briefly reviewed and technical and biological problems associated with this procedure are considered. Prenatal diagnosis of Fragile X syndrome using molecular genetic techniques is now a well established procedure, with the only significant problem being the inability to accurately predict phenotype in female fetuses with full mutations. Few prenatal diagnoses of Fragile XE non-specific mental retardation have been recorded. In principle the technical aspects of such a prenatal diagnosis should be little different from those for Fragile X syndrome. Incomplete knowledge of the phenotypic effect of the full mutation in males and females would make phenotypic prediction for any fetus shown to have such a mutation very difficult. At this stage all that could be determined with precision is that the mutation was present or absent in the fetus. Possible consequences of this are discussed.

Female↗
PubMed1996

Identification of the gene FMR2, associated with FRAXE mental retardation.

Five folate-sensitive fragile sites have been characterized at the molecular level (FRAXA, FRAXE, FRAXF, FRA16A and FRA11B). Three of them (FRAXA, FRAXE and FRA11B) are associated with clinical problems, and two of the genes (FMR1 in FRAXA and CBL2 in FRA11B) have been identified. All of these fragile sites are associated with (CCG)n/(CGG)n triplet expansions which are hypermethylated beyond a critical size. FRAXE is a rare folate sensitive fragile site only recently recognized. Its cytogenetic expression was found to involve the amplification of a (CCG)n repeat adjacent to a CpG island. Normal alleles vary from 6 to 25 copies. Expansions of greater than 200 copies were found in FRAXE expressing males and their FRAXE associated CpG island was fully methylated. An association of FRAXE expression with concurrent methylation of the CpG island and mild non-specific mental handicap in males has been reported by several groups. We now report the cloning and characterization of a gene (FMR2) adjacent to FRAXE. Elements of FMR2 were initially identified from sequences deleted from a developmentally delayed boy. We correlate loss of FMR2 expression with (CCG)n expansion at FRAXE, demonstrating that this is a gene associated with the CpG island adjacent to FRAXE and contributes for FRAXE-associated mild mental retardation.

Amino Acid Sequence↗
PubMed1996

Suggestion of a major gene for familial febrile convulsions mapping to 8q13-21.

Febrile convulsions affect 2 to 5% of all children under the age of 5 years. These convulsions probably have a variety of causes, but a genetic component has long been recognised. A large and remarkable family is described in which febrile convulsions appear to result from autosomal dominant inheritance at a single major locus. A gene for febrile convulsions was excluded from regions of previously mapped epilepsy genes and extension of exclusion mapping, using microsatellite markers, to the entire genome implied that a locus on chromosome 8q13-21 may be involved. Linkage analysis of markers on chromosome 8 gave a multipoint lod score of 3.40, maximised over different values of penetrance and phenocopy rate, for linkage between the gene for febrile convulsions and the region flanked by markers D8S553 and D8S279. This lod score was calculated assuming the disease has a penetrance of 60% and a phenocopy rate of 3%. Although there was no indication of linkage other than to markers on chromosome 8, linkage remains suggestive rather than significant because of the maximisation procedure applied. The support for linkage involving a major gene, as opposed to an alternative hypothesis of a complex inheritance pattern, relied upon the assumption of low penetrance.

Adolescent↗
PubMed1995

Genetic linkage studies in familial frontal epilepsy: exclusion of the human chromosome regions homologous to the El-1 mouse locus.

Familial frontal epilepsy has been recently described in six pedigrees. All families reported show autosomal dominant inheritance with incomplete penetrance. Affected individuals develop predominantly nocturnal seizures with frontal lobe semiology. In 1959, a genetic mouse model for partial epilepsy, the El mouse, was reported. In the El mouse, a major seizure susceptibility gene, El-1, segregates in an autosomal dominant fashion and has been localized to a region distal to the centromere of mouse ch 9. Comparative genetic maps between man and mouse have been used to predict the location of several human disease genes. The El-1 locus in the mouse is homologous to human chromosomes 3p23-p21.2, 3p11.2-q11.2, 3q21-q25.3, 6p12-q12 and 15q24. Polymorphic microsatellite markers covering these candidate regions were used for genotyping individuals in the three larger families ascertained, one of which is French-Canadian and two are Australian. Significant negative two-point and multipoint lod scores were obtained separately for each family, thus excluding linkage with the candidate regions on chromosomes 3, 6 and 15.

Animals↗
PubMed1995

Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2.

The epilepsies comprise a group of syndromes that are divided into generalized and partial (focal) types. Familial occurrence has long been recognized but progress in mapping epilepsy genes has been slow except for rare cases where the inheritance is easily determined from classical genetic studies. Linkage is established for three generalized syndromes: the EBN1 and EBN2 genes for benign familial neonatal convulsions (BFNC) map to chromosomes 20q and 8q (refs 2-5), the EPM1 gene for Unverricht-Lundborg disease maps to 21q (ref. 6) and the gene for the northern epilepsy syndrome maps to 8p (ref. 7). A claim for linkage of the EJM1 gene for the common generalized syndrome of juvenile myoclonic epilepsy to 6p is currently in dispute. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was recently described in five families. We now report the chromosomal assignment, to 20q13.2, for the gene for ADNFLE in one large Australian kindred with 27 affected individuals spanning six generations.

Chromosomes, Human, Pair 20↗
PubMed1995

A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.

Amino Acid Sequence↗
PubMed1995

Genetic adaptation to captivity and inbreeding depression in small laboratory populations of Drosophila melanogaster.

The rate of adaptation to a competitive laboratory environment and the associated inbreeding depression in measures of reproductive fitness have been observed in populations of Drosophila melanogaster with mean effective breeding size of the order of 50 individuals. Two large wild-derived populations and a long-established laboratory cage population were used as base stocks, from which subpopulations were extracted and slowly inbred under crowded conditions over a period of 210 generations. Comparisons have been made of the competitive ability and reproductive fitness of these subpopulations, the panmictic populations produced from them by hybridization and random mating and the wild- or cage-base populations from which they were derived. After an average of approximately 180 generations in the laboratory, the wild-derived panmictic populations exceeded the resampled natural populations by 75% in fitness under competitive conditions. The cage-derived panmictic population, after a total of 17 years in the laboratory, showed a 90% superiority in competitive ability over the corresponding wild population. In the inbred lines derived from the wild-base stocks, the average rate of adaptation was estimated to be 0.33 +/- 0.06% per generation. However, the gain in competitive ability was more than offset by inbreeding depression at an initial rate of approximately 2% per generation. The effects of both adaptation and inbreeding on reproductive ability in a noncompetitive environment were found to be minor by comparison. The maintenance of captive populations under noncompetitive conditions can therefore be expected to minimize adaptive changes due to natural selection in the changed environment.

Adaptation, Biological↗
PubMed1995

Reduced genetic load revealed by slow inbreeding in Drosophila melanogaster.

The rate of decline in reproductive fitness in populations of Drosophila melanogaster inbred at an initial rate of approximately 1% per generation has been investigated under both competitive and noncompetitive conditions. Breeding population size was variable in the inbred lines with an estimated harmonic mean of 66.7 +/- 2.2. Of the 60 lines maintained without reserves, 75% survived a period of 210 generations of slow inbreeding and were then rapidly inbred by full-sib mating to near-homozygosity. The initial rate of inbreeding was estimated to be 0.96 +/- 0.16% per generation, corresponding to an effective population size of approximately 50. However, the rate of inbreeding declined significantly with time to average only 0.52 +/- 0.08% per generation over the 210 generation period, most likely due to associative overdominance built up by genetic sampling and selection in the small populations. The total inbreeding depression in fitness was estimated to be 87 +/- 3% for competitive ability and 27 +/- 5% for fitness under uncrowded conditions, corresponding to rates of decline of 2.0 +/- 0.3 and 0.32 +/- 0.07%, respectively, per 1% increase in the inbreeding coefficient. The frequency of lethal second chromosomes in the resultant near-homozygous lines was of the order of 5%, lethal free second chromosomes showed a mean viability under both crowded and uncrowded conditions of approximately 95%, and their population cage fitness was 60% that of Cy/+ heterozygotes. It can be concluded that homozygous genotypes from which deleterious genes of major effect have been eliminated during slow inbreeding may show far less depression in reproductive fitness than suggested by earlier studies of wild chromosome homozygotes. The loss in fitness due to homozygosity throughout the entire genome may be as little as 85-90% under competitive conditions, and 25-30% in an optimal environment.

Animals↗
PubMed1995

Localization of craniosynostosis Adelaide type to 4p16.

Craniosynostosis Adelaide type is a rare autosomal dominant syndrome associated with digital abnormalities. Linkage mapping was carried out excluding allelism to Saethre-Chotzen syndrome at 7p21, craniosynostosis Boston type at 5q34-q35, Jackson-Weiss and Crouzon syndromes at 10q24-q25 and Pfeiffer syndrome mapping near 8cen. Exclusion mapping was extended to the entire genome until linkage to chromosome 4 was detected. A maximum two-point lod score of 6.2 (theta = 0.0) was obtained with D4S412. The gene responsible for craniosynostosis Adelaide type was localized to 4p16, telomeric to D4S394. This region contains two plausible candidate genes, the MSX1 (HOX7) homeobox gene and the FGFR3 fibroblast growth factor receptor gene.

Chromosome Mapping↗
PubMed1995

FRAXE and mental retardation.

Mental impairment and instability of the CCG repeat at FRAXE is described in six kindreds. Cosegregation of FRAXA and FRAXE was found within one of these kindreds. Cytogenetic expression of FRAXE was shown to skip a generation when associated with a reduction in size of the CCG expansion when transmitted through a male; however, in general, transmission occurred through females and a copy number increased from one generation to the next. In these respects the behaviour of FRAXE paralleled that of FRAXA. A relationship between FRAXE and non-specific mental impairment is strongly suggested by the occurrence in these families of more mentally impaired male and female carriers, after removal of index cases, than could reasonably be expected by chance.

Adolescent↗
PubMed1995

X linked fatal infantile cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome.

A number of families with X linked dilated cardiomyopathy with onset in infancy or childhood have now been described, with varying clinical and biochemical features. Of these, one condition, Barth syndrome (BTHS), can be diagnosed clinically by the characteristic associated features of skeletal myopathy, short stature, and neutropenia, but not all of these features are always present. Molecular genetic studies have delineated the gene for BTHS, which maps to distal Xq28, from the gene for so called X linked dilated cardiomyopathy (XLCM), a teenage onset dilated cardiomyopathy, recently mapped to the 5' portion of the dystrophin locus at Xp21. We report a large family in which male infants have died with congenital dilated cardiomyopathy, and there is a strong family history of unexplained death in infant males over at least four generations. Death always occurred in early infancy, without development of the characteristic features associated with Barth syndrome. Molecular analysis localised the gene in this family to Xq28 with lod scores of 2.3 at theta = 0.0 with dinucleotide repeat markers, p26 and p39, near DXS15 and at F8C. The proximal limit to the localisation of the gene in this family is defined by a recombinant at DXS296, while the distal limit could not be differentiated from the telomere. This localisation is consistent with a hypothesis of allelic and clinical heterogeneity at the BTHS locus in Xq28.

Alleles↗
PubMed1995

Overlapping submicroscopic deletions in Xq28 in two unrelated boys with developmental disorders: identification of a gene near FRAXE.

Two unrelated boys are described with delay in development and submicroscopic deletions in Xq28, near FRAXE. Molecular diagnosis to exclude the fragile X (FRAXA) syndrome used the direct probe pfxa3, together with a control probe pS8 (DXS296), against PstI restriction digests of DNA. Deletions were detected initially by the control probe pS8, which is an anonymous fragment subcloned from YAC 539, within 1 Mb distal to FRAXA. Further molecular analyses determined that the maximum size of the deletion is < 100 kb in one boy (MK) and is wholly overlapped by the deletion of up to approximately 200 kb in the other (CB). These deletions lie between the sequences detected by the probe VK21C (DXS296) and a dinucleotide repeat VK18AC (DXS295). The patient MK had only speech delay with otherwise normal development, while patient CB had global developmental delay that included speech delay. Detection of overlapping deletions in these two cases led to speculation that coding sequences of a gene(s) important in language development may be affected. Hybridization of the pS8 and VK21A probes to zooblots revealed cross-species homology. This conservation during evolution suggested that this region contains sequences with functional significance in normal development. The VK21A probe detected a 9.5-kb transcript in placenta and brain and a smaller, 2.5-kb, transcript in other tissues analyzed.

Child, Preschool↗
PubMed1994

Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1.

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uniformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible.

Adolescent↗
PubMed1994

Localisation of the gene for X-linked reticulate pigmentary disorder with systemic manifestations (PDR), previously known as X-linked cutaneous amyloidosis.

X-linked reticulate pigmentary disorder (PDR), previously reported as X-linked cutaneous amyloidosis (MIM#301220), is characterized by brown pigmentation of the skin which follows the lines of Blaschko in females but appears as reticulate sheets in males. Males may suffer severe gastrointestinal disorders in infancy with failure to thrive and early death. Nowadays symptomatic treatment allows survival and other manifestations may appear such as corneal dystrophy with severe photophobia or chronic respiratory disease. Amyloid deposition in the skin may be no more than an age-dependent secondary manifestation. The PDR gene was localised by linkage analysis to Xp21-p22. The background genetic map is Xpter-DXS996-22.5-DXS207-3.3-DXS999-3.3-DXS36 5-14.2-DXS989-4.1-3'DMD-3.5- DXS997-1.0-STR44-9.3-DYSI-2.3-DXS1068-11.0-DX S228 with distances between markers given in cM. Recombinants detected with DXS999 distally and DXS228 proximally, define the limits to the localisation. Linkage was found with several markers within this interval. Peak lod scores of 3.21 at theta = 0.0 were obtained between PDR and DXS989 and between PDR and 5'DYSI within the dystrophin locus.

Amyloidosis↗
PubMed1994

Regional localisation of a non-specific X-linked mental retardation gene (MRX19) to Xp22.

A gene responsible for a non-specific form of X-linked mental retardation (MRX19) was localised by linkage analysis. Exclusions and regional localisation were made using 21 highly informative PCR-based markers along the X chromosome. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS207, DXS987 (Zmax = 3.58) and DXS999 (Zmax = 3.28) indicating that this gene is localised to the proximal portion of Xp22. Recombination between MRX19 and the flanking loci KAL and DXS989 was observed. The multipoint CEPH background map, with map distances in cM, is DXS996-1.8-KAL-19.0-DXS207-0.9-[DXS987,DXS443 ]-4.3-DXS999-3.5-DXS365-14.0-DXS989. Two other MRX disorders and two syndromal mental retardations, Coffin-Lowry syndrome and Partington syndrome, have been mapped to this region. There is a possibility that the 3 MRX disorders are the same entity. Most MRX disorders remain clustered around the pericentromeric region.

Centromere↗
PubMed1994

Jackson-Weiss syndrome: clinical and radiological findings in a large kindred and exclusion of the gene from 7p21 and 5qter.

We describe the clinical and radiological manifestations of the Jackson-Weiss syndrome (JWS) in a large South Australian kindred. Radiological abnormalities not previously described in the hands include coned epiphyses, distal and middle phalangeal hypoplasia, and carpal bone malsegmentation. New radiological findings in the feet include coned epiphyses, hallux valgus, phalangeal, tarso-navicular and calcaneonavicular fusions, and uniform absence of metatarsal fusions. Absence of linkage to eight markers along the short arm of chromosome 7 excluded allelism between JWS and Saethre-Chotzen syndrome at 7p21. No linkage was detected to D5S211, excluding allelism to another recently described cephalosyndactyly syndrome mapping to 5qter.

Alleles↗