De novo COX2 mutation in a LHON family of Caucasian origin: implication for the role of mtDNA polymorphism in human pathologyZhadanov, Sergey; Atamanov, Vasiliy; Zhadanov, Nikolay; Schurr, Theodore
doi: 10.1007/s10038-005-0340-ypmid: 16418878
Recent studies suggest that certain mutations with phylogeographic importance as haplogroup markers may also influence the phenotypic expression of particular mitochondrial disorders. One such disorder, Leber’s hereditary optic neuropathy (LHON), demonstrates a clear expression bias in mtDNAs belonging to haplogroup J, a West Eurasian maternal lineage defined by polymorphic markers that have been called ‘secondary’ disease mutations. In this report, we present evidence for a de novo heteroplasmic COX2 mutation associated with a LHON clinical phenotype. This particular mutation—at nucleotide position 7,598—occurs in West Eurasian haplogroup H, the most common maternal lineage among individuals of European descent, whereas previous studies have detected this mutation only in East Eurasian haplogroup E. A review of the available mtDNA sequence data indicates that the COX2 7598 mutation occurs as a homoplasic event at the tips of these phylogenetic branches, suggesting that it could be a variant that is rapidly eliminated by selection. This finding points to the potential background influence of polymorphisms on the expression of mild deleterious mutations such as LHON mtDNA defects and further highlights the difficulties in distinguishing deleterious mtDNA changes from neutral polymorphisms and their significance in the development of mitochondriopathies.
Association of IL8, CXCR2 and TNF-α polymorphisms and airway diseaseMatheson, Melanie; Ellis, Justine; Raven, Joan; Walters, E.; Abramson, Michael
doi: 10.1007/s10038-005-0344-7pmid: 16429233
Chronic obstructive pulmonary disease (COPD) is a disease characterised by inflammation of the peripheral airways involving many inflammatory cells and mediators. IL8 is an important inflammatory mediator that is responsible for the migration and activation of neutrophils. Cellular activity of IL8 is mediated by the receptor CXCR2, and transcription of IL8 is controlled by the cytokine tumour necrosis factor (TNFα). The aim of our study was to investigate the influence of single nucleotide polymorphisms in IL8, CXCR2 and TNF-α on lung function and respiratory symptoms in subjects from Melbourne, Australia. A total of 1,232 participants completed a detailed respiratory questionnaire, spirometry and measurement of gas transfer. Genotyping for the IL8 -251 T→A, CXCR2 +785C→T and TNF-α -308G→A polymorphisms was performed using the tetra-primer ARMS-PCR method. The TNF-α A allele was associated with a reduced FEF25–75 (P=0.03). Inheritance of the CXCR2 T allele was associated with significantly higher diffusing capacity (P=0.03) and FEF25–75 (P=0.02). No association with the IL8 -251 polymorphism was found. Our results suggest that TNF-α is associated with COPD-related phenotypes and the CXCR2 +785 SNP may be important in protecting against pulmonary inflammation. These genes may be important candidates in the modulation of the inflammatory response in the airways.
Biochemical data in ornithine transcarbamylase deficiency (OTCD) carrier risk estimation: logistic discrimination and combination with genetic informationOexle, Konrad
doi: 10.1007/s10038-005-0345-6pmid: 16453063
One-fifth of the gene mutations causing ornithine transcarbamylase deficiency cannot be detected. In such cases carrier risk estimation must refer to biochemical data—such as increased plasma glutamine concentration or increased orotidine excretion after allopurinol load —although these parameters do not yield a definite diagnosis. Here, I derive odds for carrier risk estimation from published data, i.e. from mean and standard deviation of glutamine concentrations in carriers and noncarriers, assuming normal distributions, and from allopurinol test results in individual carriers and noncarriers using logistic regression. I show how such biochemical information may be combined with genetic information, thus demonstrating the usefulness of biochemical data. The necessity to assess individual results in larger proband groups and to consider possible correlations between different parameters is indicated.
Molecular insights into the origins of the Shompen, a declining population of the Nicobar archipelagoTrivedi, Rajni; Sitalaximi, T.; Banerjee, Jheelam; Singh, Anamika; Sircar, P.; Kashyap, V.
doi: 10.1007/s10038-005-0349-2pmid: 16453062
The Shompen, one of the most isolated and poorly understood contemporary hunter–gatherer populations, inhabit Great Nicobar Island, the southernmost island of the Nicobar archipelago. Morphological imprints in the Shompen were interpreted to favour a mixed Indo-Chinese, Malay, Negrito and Dravidian origin. Analyses of the mitochondrial, Y-chromosomal and autosomal gene pool of contemporary Shompen have revealed low diversity, illustrating a founder effect in the island population. Mitochondrial sequence analyses revealed the presence of two haplogroups of R lineage: B5a, and a newly defined clade, R12. Y-chromosomal analyses demonstrated the occurrence of a single lineage found predominantly in Austro-Asiatic speakers across Asia. With the different types of genetic markers analysed, the Shompen exhibit varying levels of genetic relatedness with the Nicobarese, and Austro-Asiatic speakers of mainland India and Southeast Asia. These genetic analyses provide evidence that the Shompen, an offshoot of the Nicobarese, are descendants of Mesolithic hunter–gatherers of Southeast Asian origin, deriving from at least two source populations.
A rapid and reliable detection system for the analysis of PMP22 gene dosage by MP/DHPLC assayLin, Chia-Yun; Su, Yi-Ning; Lee, Chien-Nan; Hung, Chia-Cheng; Cheng, Wen-Fang; Lin, Win-Li; Chen, Chi-An; Hsieh, Sung-Tsang
doi: 10.1007/s10038-005-0350-9pmid: 16463004
Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are caused by a 1.5-Mb duplication and a deletion at chromosome 17p11.2–12 encompassing the peripheral myelin protein 22 gene (PMP22), respectively. We developed a rapid and reliable detection system for duplications/deletions of the PMP22 gene based on measurement of gene copy number. The method involves amplification of a test locus with unknown copy number and a reference locus of known copy number by multiplex PCR (MP), followed by denaturing high-performance liquid chromatography (DHPLC) or capillary electrophoresis detection to identify single copy changes. Thirty-two patients with CMT1A, 17 patients with HNPP, and 61 unaffected individuals were analyzed. Using the same competitive MP protocol, the measured PMP22 gene dosage revealed concordant results between DHPLC and capillary electrophoresis analysis. The results of the MP/DHPLC or the MP/capillary electrophoresis assay were all confirmed by PCR–restriction fragment length polymorphism analysis. We concluded that the MP/DHPLC assay is an efficient, accurate, and reliable technique for gene dosage determination of the PMP22 gene for CMT1A duplication and HNPP deletion. This technique further extends the application of DHPLC as an alternative method for the measurement of gene amplifications and heterozygous deletions in different genetic diseases.
Austronesian origin of the 27-bp deletion of the erythrocyte band 3 gene in East Sepik, Papua New Guinea inferred from mtDNA analysisTsukahara, Takahiro; Hombhanje, Francis; Lum, Jeffrey; Hwaihwanje, Ilomo; Masta, Andrew; Kaneko, Akira; Kobayakawa, Takatoshi
doi: 10.1007/s10038-005-0352-7pmid: 16429231
The 27-bp deletion in the erythrocyte band 3 gene (B3Δ27) constitutes a genetic basis for Southeast Asian and Melanesian ovalocytosis. The distribution of B3Δ27 has been interpreted to reflect malaria selection or dispersal of the recent expansion of Austronesian-speaking populations. To explore these two hypotheses, we examined eight malarious populations of the East Sepik Province of Papua New Guinea (PNG) that speak both the Austronesian and Papuan languages. The B3Δ27 allele frequencies within populations were not positively correlated with malaria endemicities. In contrast, statistically significant geographical variations in the B3Δ27 allele distribution were observed. B3Δ27 was high (0.06–0.07) in the islands, intermediate (0.02–0.03) in coastal regions, but was absent or rare (0.00–0.01) in inland populations. Furthermore, the prevalence of the mitochondrial DNA region V 9-bp deletion, associated with the Austronesian expansion, was significantly correlated with that of B3Δ27. These results suggest that B3Δ27 was introduced by Austronesian-speaking people within the past 3,500 years and susequently expanded to populations along the coasts and islands of PNG. This study highlights the contribution of population origins, patterns of gene flow, disease selection and genetic drift in determining the genetic compositions of present populations.