Journal of Human Genetics

Ganesh, Subramaniam; Puri, Rajat; Singh, Shweta; Mittal, Shuchi; Dubey, Deepti

doi: 10.1007/s10038-005-0321-1pmid: 16311711

Lafora’s disease (LD) is an autosomal recessive and fatal form of progressive myoclonus epilepsy with onset in late childhood or adolescence. LD is characterised by the presence of intracellular polyglucosan inclusions, called Lafora bodies, in tissues including the brain, liver and skin. Patients have progressive neurologic deterioration, leading to death within 10 years of onset. No preventive or curative treatment is available for LD. At least three genes underlie LD, of which two have been isolated and mutations characterised: EPM2A and NHLRC1. The EPM2A gene product laforin is a protein phosphatase while the NHLRC1 gene product malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Analyses of the structure and function of these gene products suggest defects in post-translational modification of proteins as the common mechanism that leads to the formation of Lafora inclusion bodies, neurodegeneration and the epileptic phenotype of LD. In this review, we summarise the available information on the genetic basis of LD, and correlate these advances with the rapidly expanding information about the mechanisms of LD gained from studies on both cell biological and animal models. Finally, we also discuss a possible mechanism to explain the locus heterogeneity observed in LD.

Falchi, Alessandra; Giovannoni, Laurianne; Calo, Carla Maria; Piras, Ignazio Stefano; Moral, Pedro; Paoli, Giorgio; Vona, Giuseppe; Varesi, Laurent

doi: 10.1007/s10038-005-0324-ypmid: 16307178

The existence of a genetic gradient across continents has often been highlighted. Comparisons among several genetic markers have suggested that most genes of current Europeans are descended from the Near East. During the Paleolithic period, populations were confined in refuges by the last glaciation. At the end of the Paleolithic period, European migrations began from these refuges. Our objective was to highlight these various flows, starting from well-defined isolated populations, originating mainly from western Mediterranean islands. We investigated polymorphisms in the hypervariable 1 (HVR1) zone of mitochondrial DNA (mtDNA) in many Mediterranean isolates: Andalusia, Balearic Islands, southern Corsica, Morocco, Sant’ Antioco Island, San Pietro Island, Gallura, Nuoro and Trexenta (Sardinia) and Tuscany. We have compared our findings with those from other Mediterranean populations. Occupation of the Mediterranean area from the Middle East began in the Upper Paleolithic period around 40,000 years ago, with a population diversity determined by geographical and historical factors. Of the isolates studied, the population of the Balearic Islands show genetic characteristics correlated with various European flows initiated about 5,000 years ago. The island of San Pietro, in southwest Sardinia, still preserves the genetic traces of settlement by Ligurian migrants in 1736.

Visser, Remco; Hasegawa, Tomonobu; Niikawa, Norio; Matsumoto, Naomichi

doi: 10.1007/s10038-005-0314-0pmid: 16252063

Sotos syndrome (SoS, OMIM#117550) is an overgrowth disorder characterized by excessive growth—especially in the first years of childhood—distinctive craniofacial features, and various degrees of mental retardation. Haploinsufficiency of the nuclear receptor binding SET domain containing protein 1 (NSD1) gene, due to either intragenic mutations or whole-gene microdeletions, is found in the majority of patients with SoS. However, in approximately 10–40% of patients with a typical SoS phenotype, no abnormalities are detected. In this study, hemizygous hypermethylation or genomic sequence abnormalities of the promoter region of NSD1 were hypothesized to be the underlying cause in patients with a SoS phenotype, but without confirmed NSD1 alterations. In 18 patients, including one patient with a reported hepatocellular carcinoma, the promoter region of NSD1 was analyzed. However, no hypermethylation or sequence abnormalities in the promoter region could be detected. It therefore seems unlikely that such abnormalities of NSD1 are a major culprit in patients with phenotypical SoS. Additional methods are necessary for detection of other genetic or epigenetic causes of SoS.

Kloor, Doris; Fumic, Ksenija; Attig, Sebastian; Tete, Martina; Osswald, Hartmut; Baric, Ivo; Tomiuk, Jürgen; Kömpf, Jost

doi: 10.1007/s10038-005-0315-zpmid: 16273424

Recently, a proven case of human S-adenosylhomocysteine-hydrolase (SAHH) deficiency was reported in a Croatian boy. As molecular analysis of the SAHH gene in this case revealed two different mutant alleles, we investigated the polymorphism of human SAHH in a total of 237 red blood samples from unrelated Croats using starch gel electrophoresis and an enzyme-specific staining procedure. From the relative enzymatic activity of SAHH—determined by densitometric assessment of electrophoretic patterns, and calculated on the basis of the protein concentration of the red blood cells—we detected three individuals as being heterozygous for an SAHH 0-allele. Moreover, a total of four different electromorphic SAHHs have been observed, giving allele frequencies calculated as SAHH 1=0.941, SAHH 2=0.032, SAHH 3=0.006, SAHH 4=0.015, and SAHH 0=0.006.

Tosetto, Enrica; Graziotto, Romina; Artifoni, Lina; Nachtigal, Josef; Cascone, Carmelo; Conz, Piero; Piva, Michele; Dell’Aquila, Roberto; Paoli Vitali, Ermanno; Citron, Lorenzo; Nalesso, Federico; Antonello, Augusto; Vertolli, Ugo; Zagatti, Riccardo; Lupo, Antonio;

Suzuki, Yoshihiko; Ando, Fujiko; Ohsawa, Ikuroh; Shimokata, Hiroshi; Ohta, Shigeo

doi: 10.1007/s10038-005-0318-9pmid: 16307179

The Japanese have a polymorphism in the alcohol dehydrogenase 2 gene (ADH2). The alleles of ADH2 (ADH2*1 and ADH2*2) encode more active and less active forms for ethanol metabolism, respectively. We examined whether liver damage and the insulin–glucose axis vary according to ADH2 genotype in the Japanese. The 2,232 subjects (1,126 men and 1,106 women) were recruited from a population-based prospective cohort study. Clinical evaluations including alcohol consumption, percentage of alcohol drinkers, plasma glucose, HbA1c, insulin, AST, ALT, γ-GTP, and prevalence of diabetes were compared among the ADH2 genotypes. The percentage of drinkers, alcohol consumption, AST, ALT, and γ-GTP were higher in group ADH2*1/1 than in group ADH2*1/2 or ADH2*2/2 (all P<0.05). Hence, ADH2*1/1 is associated with excess alcohol intake and liver disorders. However, the prevalence of diabetes did not differ among the three groups. For the glucose–insulin axis, we examined subjects who did not receive insulin therapy or oral anti-diabetes medication. While amounts of alcohol consumed and glucose levels were nearly the same between ADH*1/2 and ADH2*2/2, insulin concentrations were lower in ADH2*2/1 than in ADH2*2/2 (P<0.05 in men). This finding suggests that the ADH2*1 allele is associated with a lower insulin concentration when alcohol intake is light or moderate. It also suggests that the genetic effect of ADH2*1 plays an important role in alcohol drinking behavior and in the occurrence of liver injury, but the effect is so mild that it does not influence the glucose–insulin axis or prevalence of diabetes.

Ichikawa, Eisaburo; Watanabe, Akira; Nakano, Yoko; Akita, Sadanori; Hirano, Akiyoshi; Kinoshita, Akira; Kondo, Shinji; Kishino, Tatsuya; Uchiyama, Takeshi; Niikawa, Norio; Yoshiura, Koh-ichiro

doi: 10.1007/s10038-005-0319-8

Hammer, Michael; Karafet, Tatiana; Park, Hwayong; Omoto, Keiichi; Harihara, Shinji; Stoneking, Mark; Horai, Satoshi

doi: 10.1007/s10038-005-0322-0pmid: 16328082

Historic Japanese culture evolved from at least two distinct migrations that originated on the Asian continent. Hunter-gatherers arrived before land bridges were submerged after the last glacial maximum (>12,000 years ago) and gave rise to the Jomon culture, and the Yayoi migration brought wet rice agriculture from Korea beginning ~2,300 years ago. A set of 81 Y chromosome single nucleotide polymorphisms (SNPs) was used to trace the origins of Paleolithic and Neolithic components of the Japanese paternal gene pool, and to determine the relative contribution of Jomon and Yayoi Y chromosome lineages to modern Japanese. Our global sample consisted of >2,500 males from 39 Asian populations, including six populations sampled from across the Japanese archipelago. Japanese populations were characterized by the presence of two major (D and O) and two minor (C and N) clades of Y chromosomes, each with several sub-lineages. Haplogroup D chromosomes were present at 34.7% and were distributed in a U-shaped pattern with the highest frequency in the northern Ainu and southern Ryukyuans. In contrast, haplogroup O lineages (51.8%) were distributed in an inverted U-shaped pattern with a maximum frequency on Kyushu. Coalescent analyses of Y chromosome short tandem repeat diversity indicated that haplogroups D and C began their expansions in Japan ~20,000 and ~12,000 years ago, respectively, while haplogroup O-47z began its expansion only ~4,000 years ago. We infer that these patterns result from separate and distinct genetic contributions from both the Jomon and the Yayoi cultures to modern Japanese, with varying levels of admixture between these two populations across the archipelago. The results also support the hypothesis of a Central Asian origin of Jomonese ancestors, and a Southeast Asian origin of the ancestors of the Yayoi, contra previous models based on morphological and genetic evidence.

Tan, Choon-Yee; Chen, Yi-Lin; Wu, Lawrence; Liu, Chai-Fan; Chang, Wen-Tsan; Wang, Jiu-Yao

doi: 10.1007/s10038-005-0323-zpmid: 16292464

CD14 is responsible for environmental lipopolysaccharide recognition and is a positional candidate gene for allergy. We hypothesized that genetic polymorphisms in the promoter region of the CD14 gene may be associated with Dermatophagoides pteronysinnus (Der p) allergen sensitization in children. Three single nucleotide polymorphisms (SNPs) of the CD14 promoter region, C(−159)T, A(−1,145)G, and G(−1,359)T were genotyped, and analyzed in 240 randomized case–control school-age children in Taiwan. Serum concentrations of IgE and soluble CD14 (sCD14) were also assayed. We found a significant inverse correlation of sCD14 and total serum IgE levels in our study population. Moreover, sCD14 binds Der p allergen in vitro in a dose-dependent manner. The distribution of three SNPs genotypes was similar in asthmatic children and the control group. However, there was a significant difference in the distribution of genotype CD14 G(−1,359)T, but not C(−159)T, between mite-sensitive and non-sensitive children. Haplotype analysis showed strong linkage disequilibrium among these three SNPs in the CD14 promoter region. Carriers of the CD14−159C/−1,145A/−1,359T haplotype had the highest IgE and lowest sCD14 levels as compared to other haplotypes. Our results support the hypothesis that CD14 gene variants may play an important role in influencing allergen sensitization of children in Taiwan.

Portera, Giorgio; Venturin, Marco; Patrizi, Antonella; Martinoli, Emanuela; Riva, Paola; Dalprà, Leda

doi: 10.1007/s10038-005-0326-9pmid: 16328081

Recurrent and non-recurrent chromosomal rearrangements seem to reflect susceptibility to DNA rearrangements due to the presence of recombinogenic motifs in at least one partner chromosomal region. While specific genomic motifs such as AT-rich repeats, fragile sites and Alu repeats are often found in recurrent translocations, the molecular mechanisms underlying non-recurrent chromosomal rearrangements remain largely unknown. Here, we map the breakpoint region of a non-recurrent translocation, t(7;9)(q11.23;p24.3), present in a healthy woman who inherited the apparently balanced translocation from her mother and transmitted the same rearrangement to two sons—respectively healthy and aborted. Characterisation by a two-step FISH analysis, first with BAC clones and then with small locus-specific probes, restricted the breakpoint intervals to 8–10 kb. Both regions contained specific Alu sequences, which, together with the flanking low copy repeat block Ac in 7q11.23, might stimulate the translocation. We noted that, although the translocation is non-recurrent, 7q11.23 is recurrently involved in different chromosomal rearrangements, supporting the hypothesis that the 7q11.23 genomic structure is prone to recombination events.