Ring chromosome 22 and neurofibromatosis

Variable constitutional mosaicism, mos45,XY,-22/46,XY,-22,+mar/46,XY,-22,+r(22)/47,XY,-22,+r(22)+mar/ 47, XY,-22,+r(22)*2, was found in PHA-stimulated peripheral blood, in a lymphoblastoid cell line and in cultured skin fibroblasts from a mentally retarded patient with neurofibromatosis. Both the ring chromosome and the small extra marker chromosome stained positively by in situ hybridization with a chromosome 14/22-specific alphoid repeat probe. DNA dosage analysis showed constitutional loss of one copy of the arylsulfatase A gene (ARSA), consistent with its terminal location on 22q. There was no evidence of constitutional loss of D22S1 or D22S28 which flank the neurofibromatosis type 2 (NF2) locus. Analysis of two DNA samples from a skin neurofibroma indicated retainment of two copies of D22S1, whereas the results were ambiguous with respect to tumor-specific loss of one copy of D22S28. It is suggested that the development of neurofibromatosis of unclear type in two r(22) carriers might be associated with somatic mutation of the NF2 locus due to instability of the ring chromosome(s), and in analogy, that somatic mutation of either NF1 or NF2 may account for some cases of neurofibromatosis which do not meet the criteria of either NF1 or NF2. The occurrence of seminoma in the proband may be fortuitous, but could also be due to the presence of a seminoma-associated locus on chromosome 22.     

Haplotype analysis of the BRCA2 9254delATCAT recurrent mutation in breast/ovarian cancer families from Spain

A frame-shift 9254del5 mutation was independently identified in 12 families, eleven of them with Spanish ancestors, in a BRCA2 screening performed in 841 breast and/or ovarian cancer families and in 339 women with breast cancer diagnosed before the age of 40 at different centers in France and Spain. We sought to analyze in detail the haplotype and founder effects of the 9254del5 and to estimate the time of origin of the mutation. Eight polymorphic microsatellite markers and two BRCA2 polymorphisms were used for the haplotype analyses. The markers were located flanking the BRCA2 gene spanning a region of 6.1 cM. Our results suggest that these families shared a common ancestry with BRCA2 9254del5, which is a founder mutation originating in the Northeast Spanish, with an estimated age of 92 (95% CI 56-141) generations.     

Alterations of plasma antioxidants and mitochondrial DNA mutation in hair follicles of smokers

The effects of long-term smoking on mitochondrial DNA (mtDNA) deletions in hair follicles were investigated in subjects with different antioxidant capacity. Twenty-two male smokers with a smoking index of greater than 5 pack-years and without any known systemic diseases were recruited for this study. Forty healthy nonsmoking males were included as controls. We found that the concentrations of ascorbate and alpha-tocopherol and the activities of glutathione S-transferase (GST) and glutathione peroxidase in blood plasma were significantly decreased in smokers. The levels of glutathione and protein thiols in whole blood and the incidence of a 4,977 bp deletion of mtDNA (dmtDNA) in hair follicles were significantly increased in smokers. A significantly higher incidence of the 4,977 bp dmtDNA was found in smokers with plasma GST activity less than 5.66 U/l (OR = 7.2, P = 0.020). Using multiple covariate ANOVA and logistic regression, we found that age and low plasma GST activity were the only two risk factors for the 4,977 bp dmtDNA. These results suggest that smoking depletes antioxidants and causes mtDNA deletions and that plasma GST may play an important role in the preservation of the mitochondrial genome in tissue cells of smokers.     

Prenatal exclusion of choroideremia

We performed prenatal testing to predict the inheritance of choroideremia (CHM) using a linked polymorphic DNA marker, DXS95. DNA analysis of chorionic villi at the 12th week of pregnancy indicated that the allele at risk had not been passed from the heterozygous mother to the fetus. This prenatal exclusion of choroideremia was confirmed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. © 1992 Wiley-Liss, Inc.     

GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum

The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then. This study underscores the broad phenotypic spectrum by presenting two patients with de novo GATA6 mutations, both exhibiting complex cardiac defects, pancreatic, and other abnormalities. Furthermore, we provided a detailed overview of all published human genetic variation in/near GATA6 published to date and the associated phenotypes (n = 78). We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively. Other common malformations were gallbladder agenesis, congenital diaphragmatic hernia, and neurocognitive abnormalities, mostly developmental delay. Fifty‐eight percent of the mutations were de novo, and these patients more often had an anomaly of intracardiac connections, an anomaly of the great arteries, and hypothyroidism, compared with those with inherited mutations. Functional studies mostly support loss‐of‐function as the pathophysiological mechanism. In conclusion, GATA6 mutations give a wide range of phenotypic defects, most frequently malformations of the heart and pancreas. This highlights the importance of detailed clinical evaluation of identified carriers to evaluate their full phenotypic spectrum.     

非小细胞肺癌中p16 INK4／CDKN2基因的缺失和点突变

目的为了探讨周期素依赖性激酶４抑制因子基因（ｐ１６ＩＮＫ４）与肺癌发生的关系。方法采用双重ＰＣＲ－ＳＳＣＰ和序列分析方法，对３１例原发性非小细胞肺癌中ｐ１６ＩＮＫ４基因的存在状况进行了研究。结果３例存在ｐ１６基因缺失（３／３１），其中１例整个ｐ１６基因发生缺失，另两例则分别为外显子１和外显子２缺失；ｐ１６基因点突变２例（２／３１），外显子１和外显子２各一例；并发现在这五例基因异常样品中，４例（２例缺失和２例点突变）样品均为淋巴转移的非小细胞肺癌（４／２０）。结论提示ｐ１６基因失活和某些非小细胞肺癌（５／３１）的发生有关，并且可能发生在癌症的晚期。     

Family cancer histories predictive of a high risk of hereditary non-polyposis colorectal cancer associate significantly with a genomic rearrangement in hMSH2 or hMLH1

Hereditary non-polyposis colorectal cancer (HNPCC) results from inactivating germline mutations in a set of DNA-mismatch-repair genes, of which the most clinically relevant are hMSH2 and hMLH1. Computer-assisted pedigree risk assessment tools are available to assist in the calculation of an individual's likelihood of bearing such a deleterious mutation. One such tool, cancergene version 3.4 (http://www3.utsouthwestern.edu/cancergene) was used to assess the risk of a deleterious mutation in the genes hMSH2 and/or hMLH1 in a series of probands selected from a panel of 67 South-western Ontario kindred previously identified as likely candidates for HNPCC by established clinical criteria. A DNA sample isolated from peripheral blood leukocytes obtained from each of these probands was examined for genomic rearrangement using the multiplex ligation-dependent probe amplification (MLPA) method. Of the individuals calculated to have a risk of >50% of a hMSH2 or hMLH1 gene mutation by the CancerGene risk assessment tool, 69% (9/13) were shown to have a genomic rearrangement resulting in the deletion of one or more exons of one of these two genes. Family cancer histories predictive of a high risk of HNPCC significantly associate with a genomic rearrangement in hMSH2 or hMLH1.     

Hepatitis B surface antigen particles of subtypes adw and adr, and compound subtype (adwr) in symptom-free carriers in Japan.

Of sera from 1,878 Japanese blood donors who carried hepatitis B surface antigen (HBsAg), 420 were subtyped as adw (22.4%) and 1,443 as adr (76.8%); only 15 (0.8%) contained HBsAg of subtype ayw or ayr. Sera with HBsAg/adr had higher HBsAg titres than those with HBsAg/adw (geometric mean of haemagglutination titre: 10.1 +/- 2.4 vs. 9.7 +/- 2.4, p less than 0.01), and a higher prevalence of hepatitis B e antigen (24% vs. 13%, p less than 0.001). Carriers of HBsAg/adr progressively predominated over those of HBsAg/adw with increasing age. Of sera from 1,863 carriers of HBsAg/adw or HBsAg/adr, 182 (9.8%) contained HBsAg particles with both subtypic determinants in the w/r allele. The presence of w and r determinants on the same particles was ascertained by sandwiching them between monoclonal antibody with the specificity for w and that with the specificity for r. HBsAg particles of compound subtype (adwr) were found more often in sera with hepatitis B e antigen than those without it (145/403 [36.0%] vs. 37/1,460 [2.5%], p less than 0.001). Sera with HBsAg/adwr particles had HBsAg titres higher than those without them (12.4 +/- 1.9 vs. 9.7 +/- 2.3, p less than 0.001). HBsAg/adwr particles arise from phenotypic mixing of the S-gene product of wild-type virus and that of mutants with point mutations for subtypic changes. The results obtained indicated that HBV strains of subtype adr have a higher replicative activity than those of adw, and suggested that mutations in the S gene for subtypic changes would be associated with an active replication of hepatitis B virus.