Exclusion of mutations in the PRNP, JPH3, TBP, ATN1, CREBBP, POU3F2 and FTL genes as a cause of disease in Portuguese patients with a Huntington-like phenotypeCosta, Maria do; Teixeira-Castro, Andreia; Constante, Marco; Magalhães, Marina; Magalhães, Paula; Cerqueira, Joana; Vale, José; Passão, Vitorina; Barbosa, Célia; Robalo, Conceição; Coutinho, Paula; Barros, José; Santos, Manuela; Sequeiros, Jorge; Maciel, Patrícia
doi: 10.1007/s10038-006-0001-9pmid: 16858508
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor N-Oct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.
MSX1 mutations contribute to nonsyndromic cleft lip in a Thai populationTongkobpetch, Siraprapa; Siriwan, Pichit; Shotelersuk, Vorasuk
doi: 10.1007/s10038-006-0006-4pmid: 16868654
Previous studies observed that MSX1 mutations could contribute to nonsyndromic cleft lip with or without cleft palate (CL/P) in some populations. Of the proposed pathogenic mutations, the P147Q variant was predominant in Vietnamese and present in Filipino populations. We investigated whether MSX1 mutations also contribute to nonsyndromic CL/P in the Thai population. Specifically, we performed mutation analysis covering all the coding regions of the MSX1 gene for 100 Thai patients with nonsyndromic CL/P. A total of eight variant sites were identified. Six were in coding regions, including four nonsynonymous changes, 101C > G (A34G), 440C > A (P147Q), 799G > T (G267C), and 832C > T (P278S). The G267C and P278S variants were predicted to be “probably damaging” by PolyPhen, changed themselves as potential exonic splicing enhancers for serine/arginine-rich proteins, and were not present in 162 control individuals of Thai ethnic background. Unlike all of the previously reported potential missense mutations in MSX1, these two novel potential mutations were found in exon 2 on the C-terminal side of the homeodomain protein. Moreover, in contrast to previous reports, we found the P147Q variant in 8 out of 100 Thai controls and an association between the variant and CL/P in our population could not be detected, suggesting that it is not pathogenic. Our data support that MSX1 mutations are found in 2% of cases of CL/P and should be considered for genetic counseling implications, but suggest that the P147Q variant is not pathogenic.
An association between asthma and TNF-308G/A polymorphism: meta-analysisAoki, Takeshi; Hirota, Tomomitsu; Tamari, Mayumi; Ichikawa, Kunio; Takeda, Kazunori; Arinami, Tadao; Shibasaki, Masanao; Noguchi, Emiko
doi: 10.1007/s10038-006-0007-3pmid: 16865291
Tumor necrosis factor (TNF) is a potent inflammatory cytokine that contributes to airway inflammation in asthma. Previous studies have reported that a G-to-A transition at position −308 (−308G/A, also referred to as TNF-α-308*1 and 308*2 respectively), is associated with asthma, but other studies have shown conflicting results. To investigate a possible association between the TNF-308G/A polymorphism and asthma, we performed transmission disequilibrium tests and a case–control study (family samples: 495 members in 165 Japanese trio families with one asthmatic child and both parents; case–control samples: 461 Japanese asthmatic children and 465 healthy controls). To increase the sample size and power, we performed a meta-analysis of all available relevant studies, including 2,477 asthmatics and 3,217 controls. We did not find a significant association between the TNF-308G/A polymorphism and childhood atopic asthma in two independent Japanese populations (P>0.05); however, meta-analysis revealed that the TNF-308G/A polymorphism was statistically significantly associated with asthma. The combined odds ratio with a fixed effects model and with a random effects for TNF-308A was 1.46 (95% confidence interval [CI], 1.27–1.68, P=0.0000001) and 1.46 (95% CI, 1.20–1.77, P=0.00014) respectively. Our data further support the importance of the TNF region in the development of asthma.
Protan color vision deficiency with a unique order of green–red as the first two genes of a visual pigment arrayUeyama, Hisao; Tanabe, Shoko; Muraki-Oda, Sanae; Yamade, Shinichi; Ohkubo, Iwao
doi: 10.1007/s10038-006-0008-2pmid: 16874439
Normal visual pigment gene arrays on the human X chromosome have a red gene at the first and a green gene at the second positions. More than half of the arrays have additional green genes downstream, but only the first two genes of the array are likely to be expressed in the retina. An array consisting of four genes in two Japanese participants, A121 and A447, was detected either by pulsed field gel electrophoresis and subsequent Southern hybridization or by single nucleotide primer extension reaction. In both participants, the first gene of the array was green, downstream genes were red and green, and the fourth gene was green. The red gene was determined to be at the second position by comparison of polymorphic sites among the intergenic regions that had been amplified by long-range PCR. Such an array with a reverse normal order of pigment genes, green–red as the first two, has never been reported before. They were expected to have normal color vision but showed protan deficiency (protanomaly), a phenotype lacking the red pigment. The red gene had no mutations in the exons and exon/intron boundaries, but had an A−71C substitution in the promoter in both participants.
Cataracts, ataxia, short stature, and mental retardation in a Chinese family mapped to Xpter-q13.1Guo, Xiangming; Shen, Huangxuan; Xiao, Xueshan; Dai, Qilin; Li, Shiqiang; Jia, Xiaoyun; Hejtmancik, J.; Zhang, Qingjiong
doi: 10.1007/s10038-006-0009-1pmid: 16832577
Six males in a Chinese family affected by congenital cataracts, cerebellar ataxia, short stature, and mental retardation, which were tentatively named CASM syndrome. Eight female carriers in the family had cataracts alone. Linkage analysis demonstrated that the disease is transmitted through X-linked inheritance, either by setting the syndrome in males as an X-linked recessive trait, or by setting cataracts in the family as an X-linked dominant trait. The gene responsible for the syndrome is mapped to Xpter-Xq13.1, with the highest lod score of 3.91 for DXS1226, DXS991, and DXS1213 at θ = 0. Haplotype analysis identified that the allele harboring the disease gene co-segregated with all female carriers as well as affected males in the family. Clinically and genetically, the disease in this family is different from any known disease. Major features of CASM syndrome that distinguish it from other diseases are X-linked inheritance and cataracts in carrier females.
Cockayne syndrome type A: novel mutations in eight typical patientsBertola, Debora; Cao, Henian; Albano, Lilian; Oliveira, Daniela; Kok, Fernando; Marques-Dias, Maria; Kim, Chong; Hegele, Robert
doi: 10.1007/s10038-006-0011-7pmid: 16865293
Cockayne syndrome is a rare autosomal recessive neurodegenerative disorder. It is considered to be a heterogeneous condition based on complementation in cell fusion studies, with two major forms, namely CS-A and CS-B. CKN1 is the gene responsible for CS-A, whose mutations disrupt the transcription-coupled repair system of the actively transcribed DNA. Mutation analysis of the CKN1 gene in eight typical CS-A Brazilian patients from six families showed a gene alteration in all of them. We found a total of five novel mutations that were absent from healthy control subjects. Six affected subjects were simple homozygotes and two affected siblings were each compound heterozygotes. While the findings extend the range of mutations in CS-A, there is no obvious genotype-phenotype correlation across the mutational spectrum.