The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both?

The mammalian mitochondrial genome (mtDNA) is a small double-stranded DNA molecule that is exclusively transmitted down the maternal line. Pathogenic mtDNA mutations are usually heteroplasmic, with a mixture of mutant and wild-type mtDNA within the same organism. A woman harbouring one of these mutations transmits a variable amount of mutant mtDNA to each offspring. This can result in a healthy child or an infant with a devastating and fatal neurological disorder. Understanding the biological basis of this uncertainty is one of the principal challenges facing scientists and clinicians in the field of mitochondrial genetics.

Cloning, mapping and expression analysis of the sheep Wilson disease gene homologue.

Copper homeostasis in mammals is maintained by the balance of dietary intake and copper excretion via the bile. Sheep have a variant copper phenotype and do not efficiently excrete copper by this mechanism, often resulting in excessive copper accumulation in the liver. The Wilson disease protein (ATP7B) is a copper transporting P-type ATPase that is responsible for the efflux of hepatic copper into the bile. To investigate the role of ATP7B in the sheep copper accumulation phenotype, the cDNA encoding the ovine homologue of ATP7B was isolated and sequenced and the gene was localised by fluorescence in situ hybridisation to chromosome 10. The 6.3 kb cDNA encoded a predicted protein of 1444 amino acids which included all of the functional domains characteristic of copper transporting P-type ATPases. ATP7B mRNA was expressed primarily in the liver with lower levels present in the intestine, hypothalamus and ovary. A splice variant of ATP7B mRNA, which was expressed in the liver and comprised approximately 10% of the total ATP7B mRNA pool, also was isolated. The results suggest that ATP7B is produced in the sheep and that the tendency to accumulate copper in the liver is not due to a gross alteration in the structure or expression of ATP7B.

Two cases of prenatal analysis for the pathogenic T to G substitution at nucleotide 8993 in mitochondrial DNA.

We report the outcome of two prenatal analyses for the T to G mutation at nucleotide 8993 in the mitochondrial DNA. This mutation is associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) and the neurodegenerative condition, Leigh syndrome. One prospective mother was the sister of a severely affected individual, and had previously had an unaffected child and a stillborn child. The second prospective mother had two unaffected children and two affected children. The mutation was not detected in the chorionic villus sample from one fetus nor in the amniocytes from the other fetus. Both pregnancies were continued, and the resulting children were healthy at two years and five years of age. Prenatal diagnosis of this mitochondrial DNA mutation is an option likely to be acceptable to some families to prevent the birth of a child at high risk for neurological disease.

Tooth root resorption associated with a familial bone dysplasia affecting mother and daughter.

The dental findings are presented of a mother and daughter who suffer from an as yet unclassified bone dysplasia that shows features of both hereditary hyperphosphatasia and familial expansile osteolysis. Both patients have experienced progressive root resorption of permanent teeth, deafness, and high alkaline phosphatase levels. The mother has a more advanced bone dysplasia which has led to progressive skeletal deformity and bone pain. The kindred is consistent with an autosomal dominant pattern, and the mutation(s) is thought to be in chromosome 18q21-22 region. Conventional treatment strategies of root resorption offer only a poor prognosis for the dentition. Therapy using alendronate, a bisphosphonate compound and a potent inhibitor of osteoclastic activity, has reduced alkaline phosphatase levels, bone pain, and may offer an effective strategy to prevent tooth root resorption in this group of diseases.

[Ascent of the testis]. / Testikkelascens.

Testes ascending from the normal scrotal position to an undescended position is common, but not well known. The case notes of 37 boys who underwent orchidopexy between 1980 and 1994 at Nordfjordeid Hospital, Norway, were collected. None of the boys had previously undergone inguinal surgery. All patients underwent testicular examination at the time of birth. 23 boys (62%) had normally descended testes at birth but subsequently developed maldescens. According to these figures, testicular ascent is far more common than previously recorded. It is of major importance that the testicular position be examined repeatedly until the age of seven years.

The structure of a thirty-six kilobase region of the human chromosome including the fibroblast interferon gene IFN-beta.

The isolation of a human genomic cosmid hybrid containing the interferon beta gene has recently been reported (Gross et al., 1981). This hybrid was mapped using single and double digests and cross-hybridisation with the sub-cloned EcoRI and BgIII fragments. Purified fragments and subclones were used as hybridisation probes against chromosomal "Southern" blots to show that at least half of the region has been cloned without alteration. This cannot at present be confirmed for the rest of the region due to the presence of highly repetitive DNA on these cloned fragments. Sequencing data on the 5'-end of the fibroblast IFN-beta gene shows a high density of direct and inverted repeats. The IFN-beta mRNA coding region contains no intron, although the possibility of other transcription starts is not ruled out. The cloned region shows no similarities to known genomic clones containing IFN-alpha genes.