ABSTRACT
We describe 15 members of a Caucasian family with an apparently homoplasmic T-->C mutation at nucleotide position 9185 (9185T>C) in the mtDNA encoded MTATP6 (ATPase 6) gene. The clinical phenotype is extremely variable and includes late-onset Leigh syndrome (LS), isolated demyelinating peripheral neuropathy and neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP). Following recent reports of this same mutation in a single case and in a family with late-onset LS and NARP-like features, our paper emphasises the role of MTATP6 in LS and expands the associated clinical phenotype further.
Subject(s)
Family Health , Leigh Disease/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mutation , Phenotype , Adolescent , Adult , DNA Mutational Analysis , Female , Humans , Leigh Disease/physiopathology , MaleABSTRACT
BACKGROUND: Aicardi-Goutières syndrome (AGS) is an autosomal recessive, early onset encephalopathy characterised by calcification of the basal ganglia, chronic cerebrospinal fluid lymphocytosis, and negative serological investigations for common prenatal infections. AGS may result from a perturbation of interferon alpha metabolism. The disorder is genetically heterogeneous with approximately 50% of families mapping to the first known locus at 3p21 (AGS1). METHODS: A genome-wide scan was performed in 10 families with a clinical diagnosis of AGS in whom linkage to AGS1 had been excluded. Higher density genotyping in regions of interest was also undertaken using the 10 mapping pedigrees and seven additional AGS families. RESULTS: Our results demonstrate significant linkage to a second AGS locus (AGS2) at chromosome 13q14-21 with a maximum multipoint heterogeneity logarithm of the odds (LOD) score of 5.75 at D13S768. The AGS2 locus lies within a 4.7 cM region as defined by a 1 LOD-unit support interval. CONCLUSIONS: We have identified a second AGS disease locus and at least one further locus. As in a number of other conditions, genetic heterogeneity represents a significant obstacle to gene identification in AGS. The localisation of AGS2 represents an important step in this process.
Subject(s)
Basal Ganglia Diseases/genetics , Calcinosis/genetics , Chromosomes, Human, Pair 13 , Lymphocytosis/genetics , Basal Ganglia Diseases/diagnosis , Calcinosis/diagnosis , Chromosome Mapping , Cohort Studies , Consanguinity , Female , Genes, Recessive , Genetic Linkage , Genotype , Humans , Infant , Infant, Newborn , Lymphocytosis/diagnosis , Male , SyndromeABSTRACT
The Xq21.3/Yp11 homology block on the human sex chromosomes represents a recent addition to the Y chromosome through a transposition event. It is believed that this transfer of material occurred after the divergence of the hominid lineage from other great apes. In this paper we investigate the structure and evolution of the block through fluorescence in situ hybridisation, contig assembly, the polymerase chain reaction, exon trapping, sequence comparison, and annotation of sequence data. The overall structure is well conserved between the human X chromosome and the Y chromosome as well as between the X chromosomes from different primates. Although the sequence data reveal a high level of nucleotide sequence identity for the human X and Y, there are regions of significant divergence, such as that around the marker DXS214. These are presumably the consequence of multiple rearrangements during evolution and are of particular importance with respect to the potential gene content in this segment of the interval.
