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Biomedical subjects

J C Mulley

Publications and source records attributed to J C Mulley.

At least 73 records · Page 4Linked to original sources
PubMed1994

A linkage map of microsatellite markers on the human X chromosome.

The efficiency of mapping and diagnosis of X-linked disorders by linkage depends upon the existence of a high-density genetic map of polymerase chain reaction (PCR)-based markers. DXS1120, DXS1122, DXS1123, DXS1124, DXS1125, DXS1126, and DXS1153 were randomly isolated from a flow-sorted lambda bacteriophage library of the human X chromosome. The CCN (N = A or G) repeat within the androgen receptor was also found to be polymorphic and primers were designed for genotyping the CCN polymorphism in addition to the AGC polymorphism. The above markers, together with microsatellite polymorphisms at DXS237 (GMGX9), 5'DYS-II and 3'DYS MS (within the dystrophin locus), DXS538 (XL27B), PGK1P1, DXS300 (VK29AC), DXS294 (VK17AC), and DXS102 (cX38.1AC), were genotyped in the 40 CEPH reference families. One marker, DXS1153, was found to include cryptic alleles that amplify only in homozygotes and hemizygotes but not heterozygotes. A PCR-based linkage map was constructed using all of the above markers plus PCR-based markers from the CEPH database and those PCR-based markers previously typed in our laboratory: ALAS2, DXS292 (VK14AC), DXS297 (VK23AC), FRAXAC1, and FRAXAC2. The genetic map of the X chromosome incorporates 62 PCR-based marker loci, integrates the Weissenbach markers, and extends from XG near Xpter to DXS52 near Xqter, a distance of 236 cM.

Alleles↗
PubMed1993

Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28.

Barth syndrome is an X-linked disorder characterised by cardioskeletal myopathy of variable severity usually fatal in childhood, and neutropenia. We ascertained a large pedigree with affected males in 3 generations. All affected males had dilated cardiomyopathy, with endocardial fibroelastosis (EFE) in some. The locus for Barth syndrome in this family was found to be closely linked to DXS52 (z = 2.78, theta = 0.0). The family was nonrecombinant for DXS52 in distal Xq28, but recombinant for DXS374 which maps proximal to DXS52. This localised Barth syndrome distal to DXS374, confirming a previous localisation to distal Xq28. As yet there is no evidence for genetic heterogeneity of Barth syndrome.

Cardiomyopathies↗
PubMed1993

Fine genetic mapping of the Batten disease locus (CLN3) by haplotype analysis and demonstration of allelic association with chromosome 16p microsatellite loci.

Batten disease, juvenile onset neuronal ceroid lipofuscinosis, is an autosomal recessive neurodegenerative disorder characterized by accumulation of autofluorescent lipopigment in neurons and other cell types. The disease locus (CLN3) has previously been assigned to chromosome 16p. The genetic localization of CLN3 has been refined by analyzing 70 families using a high-resolution map of 15 marker loci encompassing the CLN3 region on 16p. Crossovers in three maternal meioses allowed localization of CLN3 to the interval between D16S297 and D16S57. Within that interval alleles at three highly polymorphic dinucleotide repeat loci (D16S288, D16S298, D16S299) were found to be in strong linkage disequilibrium with CLN3. Analysis of haplotypes suggests that a majority of CLN3 chromosomes have arisen from a single founder mutation.

Alleles↗
PubMed1993

Integrating maps of chromosome 16.

The recently published, detailed cytogenetic-based physical map of chromosome 16 has the highest resolution of any autosomal cytogenetic map thus far constructed. The genetic map has been integrated with the cytogenetic map to facilitate the regional localization of disease genes by linkage. Disease genes for tuberous sclerosis, familial Mediterranean fever, Rubinstein-Taybi syndrome and Morquio A syndrome have now been assigned to chromosome 16. The search for the adult polycystic kidney disease gene has recently been narrowed to the analysis of candidate loci on chromosome 16, and localization of the gene determining juvenile Batten disease has been further refined by disequilibrium mapping.

Animals↗
PubMed1993

Direct molecular diagnosis of myotonic dystrophy.

Myotonic dystrophy (DM) arises from an unstable trinucleotide (CTGn) repeat sequence within the DM locus at 19q13.3. Twenty-three myotonic dystrophy families containing 205 persons with no symptoms, minimal manifestations, classic DM or congenital DM were investigated to validate the application of the pM10M6 probe to direct molecular diagnosis. Affected family members had been diagnosed clinically and the unaffected family members had been assigned carrier probabilities close to either zero or 100%, using closely linked flanking markers. Southern analysis identified all 89 DM gene carriers as having expansions of the unstable element. PstI detected all small expansions of the repeat sequence as easily seen discrete bands; but large expansions were usually seen as diffuse smears, sometimes difficult to distinguish from lane background. EcoRI concentrated these diffuse smears, associated with somatic instability, into discrete bands which were easy to detect; but it did not resolve the smaller expansions present in 9 (10%) of the DM carriers. It is essential that PstI and EcoRI gels are run in parallel to detect all DM gene carriers. The extent of expansion of CTG correlated with age of onset and disease severity. Biopsies of various fetal tissues from two terminated pregnancies confirmed the diagnosis obtained by CVS and revealed no heterogeneity between tissues at this developmental stage. Further expansion occurred during the culture of CVS cells, indicating that direct prenatal diagnosis needs to be carried out on CVS tissue rather than on cultured cells. The intergenerational change of the repeat sequence from DM parent to DM offspring showed a significant parental sex difference for those parents with large expansions. Contraction of the unstable element was observed in the three males carrying the largest expansions and could explain why congenital DM is exclusively of maternal origin.

Female↗
PubMed1993

Integration of the cytogenetic and genetic linkage maps of human chromosome 16 using 50 physical intervals and 50 polymorphic loci.

A comprehensive genetic linkage map constructed from 50 loci represented by 68 markers was anchored to 50 cytogenetically defined intervals on human chromosome 16. The linear order of the loci on the cytogenetic map was compatible with the independently derived linear order on the genetic map. The sex-averaged genetic length is 164.5 cM, with an average distance between loci of 3.3 cM. Sex-specific distances are 132.8 cM in males and 201.8 cM in females. This is the first detailed synthesis of genetic and cytogenetic maps for any human chromosome and is the first step in correlating the genetic and physical maps of this chromosome. The combined map, containing 15 loci with a minimum heterozygosity of 60% and 6 PCR-formatted microsatellite markers, will be useful for assignment and regional localization of disease genes to this chromosome.

Chromosome Mapping↗
PubMed1993

A microsatellite marker within the duplicated D16S79 locus has a null allele; significance for linkage mapping.

The dinucleotide repeat 16AC66f3 was characterised from D16S79A within a duplicated section of 16p13.11, which is duplicated on all normal chromosome 16's. This marker has a common null allele caused by polymorphism within one of the primer sites. A redesigned primer overcame this problem; however, this allowed amplification of two dinucleotide repeats, at D16S79A and D16S79B, with an overlapping and uninterpretable distribution of alleles. Thus, the 16AC66F3 marker with a null allele is potentially useful for linkage mapping, as it avoids the ambiguity associated with the genotyping of homologous AC repeats at this duplicated locus. The distribution of additional D16S79 RFLPs flanking FRA16A is clarified.

Alleles↗
PubMed1993

Genotype-phenotype relationships in fragile X syndrome: a family study.

Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of > or = 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < delta < or = 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample.

Adolescent↗
PubMed1993

Refined genetic localization for central core disease.

Central core disease (CCO) is an autosomal dominant myopathy clinically distinct from malignant hyperthermia (MHS). In a large kindred in which the gene for CCO is segregating, two-point linkage analysis gave a maximum lod score, between the central core disease locus (CCO) and the ryanodine receptor locus (RYR1), of 11.8, with no recombination. Mutation within RYR1 is responsible for MHS, and RYR1 is also a candidate locus for CCO. A combination of physical mapping using a radiation-induced human-hamster hybrid panel and of multipoint linkage analysis using the Centre d'Etude du Polymorphisme Humain families established the marker order and sex-average map distances (in centimorgans) on the background map as D19S75-(5.2)-D19S9-(3.4)-D19S191-(2.2)-RYR1-(1.7)-D19S190-(1.6)-D19S47-(2.0)- CYP2B. Recombination was observed between CCO and the markers flanking RYR1. These linkage data are consistent with the hypothesis that CCO and RYR1 are allelic. The most likely position for CCO is near RYR1, with a multipoint lod score of 11.4, in 19q13.1 between D19S191 and D19S190, within the same interval as MHS (RYR1).

Alleles↗
PubMed1993

Incidence and origin of "null" alleles in the (AC)n microsatellite markers.

Twenty-three (AC)n repeat markers from chromosome 16 were typed in the parents of the 40 CEPH (Centre d'Etude du Polymorphisme Humain) families. Where parents were informative, the entire families were then typed. There were seven markers in which null alleles were demonstrated, as recognized by the apparent noninheritance, by a sib, of a parental allele. Four of these markers showed a null allele in a single sibship, while in the other three at least 30% of the CEPH sibships were shown to have a null allele segregating. One null allele was sequenced and shown to be the result of an 8-bp deletion occurring within the priming sequence for PCR amplification of the (AC)n repeats. In gene mapping or in application to diagnosis, the presence of a segregating null allele will not corrupt the linkage data but could result in loss of information. In isolated instances a segregating null allele may be interpreted as nonpaternity. The presence of a null allele may generate misleading data when individuals are haplotyped to determine the presence of linkage disequilibrium with a disease gene.

Alleles↗
PubMed1992

A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1.

A CA dinucleotide repeat polymorphism has been identified for the skeletal muscle alpha-actinin gene ACTN2. The observed heterozygosity is 44% (predicted heterozygosity 50%, PIC 0.47). This polymorphic marker has been localized between D1S74 and D1S103 on the multipoint linkage map of chromosome 1 at a position 44.4 cM from the most distal marker D1S68 at 1 qter.

Actinin↗
PubMed1992

Identification of a highly polymorphic marker within intron 7 of the ALAS2 gene and suggestion of at least two loci for X-linked sideroblastic anemia.

We have identified a compound dinucleotide repeat within intron 7 of the human erythroid 5-aminolevulinate synthase (ALAS2) gene with a minimum of 9 alleles and heterozygosity of 78%. ALAS2 was placed on the multipoint linkage map of the X chromosome in the pericentromeric region with the locus order: pter-(DXS255, TFE3, DXS146)-(DXS14, ALAS2, DXZ1)-AR-(DXS153, DXS159)-qter. No recombination was observed between ALAS2 and the centromere marker DXZ1. As ALAS2 has recently been shown to be the defective locus in X-linked pyridoxine-responsive sideroblastic anemia (PRSA), the ALAS2 marker has allowed placement of the gene for PRSA into the multipoint linkage map of the X chromosome. With the previous exclusion of close linkage between DXS14 and sideroblastic anemia with ataxia, our data show that there are at least two loci for X-linked sideroblastic anemia.

5-Aminolevulinate Synthetase↗
PubMed1992

X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male.

Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗
PubMed1992

Report on the X-linked lymphoproliferative disease in an Australian family.

X-linked lymphoproliferative disease is characterized by immune deficiency, particularly to the Epstein-Barr virus and by a tendency to develop fatal infectious mononucleosis, acquired hypogammaglobulinaemia or malignant lymphoma. This disorder has been diagnosed in three boys, two brothers and a maternally related cousin, residing in Australia. The proband presented at 6 years of age with fulminating infectious mononucleosis. His 9 year old male cousin had developed an ileal Burkitt lymphoma one year earlier. Immunological and molecular genetic evidence is presented to support our view that his younger sibling is also affected with this condition. DNA linkage studies using probes to DXS10 and DXS37 provide confirmatory evidence for the diagnosis in the proband's brother and information on carrier status in female family members.

Agammaglobulinemia↗