Biomedical subjects
Publications and source records attributed to J C Mulley.
Gene loci for phosphoglycolate phosphatase and hydroxyacyl glutathione hydrolase were localized within human chromosome band 16p13.3. This result was determined by the electrophoretic detection of enzymes from a human x mouse somatic cell panel, the members of which carried portions of human chromosome 16 with precisely defined breakpoints.
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Polymorphic DNA markers located in bands 16q13, 16q21 and 16q22 were examined for recombination with FRA16B, the fragile site at 16q22.100. A tight linkage cluster D16S10-FRA16B-D16S4-HP was established. There were no recombinants (theta = 0.0, z = 8.3) between D16S10 and D16S4, which flank FRA16B. The markers D16S10 and D16S4 are in close proximity on the genetic map and delineate a small chromosomal segment, which contains the distamycin A-inducible fragile site.
Physical mapping of 13 different breakpoints on the short arm of chromosome 16 using previously mapped probes and the subsequent mapping of additional probes enabled the division of this portion of the chromosome into six different intervals. D16S94 was mapped between HBA and D16S80 and is closer to PKD1 than either HBA or D16S80. A tight linkage group which includes FRA16A, D16S8, and D16S79 was identified. Seven breakpoints, including FRA16A, could not be separated by probe localizations. This study provides the basis for the development of detailed maps of the short arm of chromosome 16.
Forty-three unrelated South Australian boys diagnosed as having either Duchenne or Becker muscular dystrophy were screened for deletions using DNA probes to the dystrophin gene. For the 35 boys with Duchenne muscular dystrophy, the deletion frequency was 43% using a simplified probing strategy based on the probes Cf56a, Cf56b, pERT87-15 and XJ (XJ1.1 or XJ2.3). The corresponding deletion frequency for the eight boys with Becker muscular dystrophy was 38%. Members of families in which these disorders result from a deletion can now choose to prevent the birth of further affected boys, using an accurate prenatal test for the specific mutation occurring within the family. Deletion analysis also has the potential to clarify the carrier status of women in these families.
We describe a man with Becker muscular dystrophy whose weakness was minimal in contrast to that of his more severely affected nephews. This man had a Klinefelter karyotype (47,XXY) and his mild symptoms may be attributed to him being heterozygous for the muscular dystrophy gene. This is the first report of a person with both Klinefelter's syndrome and Becker muscular dystrophy. This combination may be one explanation for the variable expression of X linked muscular dystrophy noted in some pedigrees.
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A family in which the gene for myotonic dystrophy is segregating was tested with a DNA probe to the apolipoprotein-C2 (APOC2) gene. The APOC2 gene is linked closely to the myotonic dystrophy (DM) gene and can be used as a marker to follow the transmission of the DM gene within families. Results from DNA-marker studies were combined with information from clinical, ophthalmological and electromyographic examinations, with age-dependent penetrance and a recombinant frequency of 4% between the genes for myotonic dystrophy and apolipoprotein C2 being taken into account. The chance that an individual had inherited the gene for myotonic dystrophy was determined by means of the computer program, LINKAGE. This analysis altered dramatically the assessed risk that certain individuals in the family were carrying the DM gene. For four individuals in the family, the previous risks of 50% for each member were reduced to 0.9%, 0.9% and 0.2%, respectively, in three cases and increased to 91% in the fourth case. The importance of a complete clinical evaluation of potential gene carriers who donate blood for a DNA-linkage study is stressed.
Suppression of Lutheran blood group expression is usually associated with an autosomal dominant suppressor gene In(Lu) which results in the rare Lu(a--b--) phenotype. X-linked recessive suppression can also occur under the control of the XS locus with normal (XS1) and suppressor (XS2) alleles. The only known kindred with XS2 segregating was examined for polymorphic DNA markers with known regional localisations on the X chromosome. Two point linkage analysis suggested linkage of XS to DXS14 (p58.1) with theta = 0.00, z = 1.96. DXS14 is situated near the centromere at Xp11. Recombinants with DXS84 (distal to DXS14 on Xp) and recombinants with DXYS1 (pDP34) (on the proximal part of Xq) suggests a localisation for XS near the centromere, between DXS84 and DXYS1 (Xp21.2-Xq21.1). Linkage to a marker on the X chromosome confirms the original assignment of XS to the X chromosome, which was based on pedigree inspection from this family.
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The fragile site, FRA16B, at 16q22.100 and four different translocations with breakpoints at 16q22.102, 16q22.105, 16q22.108, and 16q22.3 were used to locate and order DNA probes. This was achieved by Southern analysis of a somatic cell hybrid panel containing portions of chromosome 16 and by in situ hybridization. The anonymous DNA fragments D16S6, D16S10, and D16S11 were proximal to FRA16B and located at 16q13----q22.100. D16S4 and LCAT were located at 16q22.100----q22.102. TAT and HP were located at 16q22.105----q22.108. CTRB was located distal to 16q22.105 and therefore is in the distal half of 16q22. The order of markers in this region was determined as centromere-D16S6, D16S11, D16S10, MT-FRA16B-D16S4, LCAT-HP,TAT,CTRB-APRT- telomere. Linkage studies to determine map distances between the closest markers flanking the fragile site are now in progress.
Thirty-four Duchenne and Becker muscular dystrophy families were initially ascertained from South Australia. These have been tested systematically with the DNA probes XJ1.1 and pERT87-15. DNA results from 21 informative families have been combined with results of CK testing. Pedigree analysis was carried out using the computer program LINKAGE to provide risk figures to potential female carriers. This simple approach separated potential carriers into low or high risk classes (familial cases) or low or moderate risk classes (isolated cases). No prenatal diagnoses were carried out. The detection of deletions in two probands out of 34 makes possible definitive prenatal diagnosis in those families. For the remaining families, prenatal diagnosis could only be offered in terms of a probability statement after linkage analysis. Risk figures presented from hypothetical pedigrees demonstrated that prenatal diagnosis by linkage usually provided reasonable reliability only where informative flanking markers are used.
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Linkage data using the markers DXS51, F9, DXS15, and DXS52 are presented from 14 pedigrees segregating with the fragile X. Cytogenetic and DNA data were combined by two- or three-point linkage analysis for estimation of lod scores and carrier probabilities in potential carriers. Recombination frequencies (theta) corresponding to maximum z scores (zeta) were obtained for DXS51 (zeta = 3.45, theta = 0.0), DXS15 (zeta = 0.40, theta = 0.06), F9 (zeta = 3.15, theta = 0.09), and DXS52 (zeta = 3.60, theta = 0.11) with the fragile X. Considerable alterations to carrier probabilities occurred in some cases, especially when flanking markers were informative. The chance of mentally impaired offspring was reduced to 1% for five of eight women with prior carrier probabilities of 32%. Three pedigrees were identified in which mutation had possibly occurred. An alternative explanation for two of these was inheritance of the fragile X from normal males and for the other inheritance from a clinically normal woman. Probabilities were computed for each of these alternatives.
The parental origin of five X isochromosomes were determined using 11 DNA markers. The isochromosome was derived from a maternal X chromosome in three cases and from a paternal X chromosome in two. Unexpected heterozygosity was detected for the proximal Xp region in one individual in whom the i(Xq) chromosome was paternally derived. This was confirmed by in situ hybridisation. A mode of formation of isochromosomes by breakage and reunion between the sister chromatids of the arms of an X chromosome is proposed to account for this. Sister chromatid breakage and reunion can be considered as a significant mechanism for the origin of i(Xq) chromosomes.
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The regional localisation of the alpha globin (HBA) complex on the short arm of chromosome 16 was investigated by in situ hybridisation, Southern blot analysis, and linkage analysis using the fragile site at 16p12.3 (FRA16A) and translocation breakpoints within band 16p13.1. HBA was found to be distal to the two translocation breakpoints within band 16p13.1 and not closely linked to FRA16A. In situ hybridisation to the distal portion of the fragment on metaphase chromosomes expressing the fragile site and the observation of considerable recombination between FRA16A and HBA supports a localisation for HBA closer to the telomere than to FRA16A, at 16p13.2----pter.