P53 germ line haplotypes associated with increased risk for colorectal cancer

Three p53 DNA polymorphisms (BstU I and Msp I restriction fragmentlength polymorphisms (RFLPs) in exon 4 and intron 6 respectively,and a 16 bp duplication in intron 3) and their haplotype combinationswere studied in patients with colorectal cancer and comparedwith patients with ulcerative colitis and healthy controls.There were only minor differences between patients with ulcerativecolitis and controls, the only significant difference was observedin the distribution of BstU I-Msp I haplotypes. When singlepolymorphisms were studied, a significantly lower frequencyof the 16 bp duplication was found in patients with colorectalcancer. The protective effect of the 16 bp duplication was morepronounced in haplotype combinations with the BstU I Al andMsp I Al alleles, whereas these alleles in combination withthe 16 bp Al allele (no duplication) were associated with anincreased risk for colorectal cancer. The genotypic combinationBstU I 2–1, 16 bp 1–1, Msp I 2–1 was foundin 8.4% of cases among patients with colorectal cancer and 0.5%of cases in the controls (odds ratio = 18.8). The extended haplotyperesponsible for the high cancer risk of this genotype appearsto be BstU I Al-16 bp Al-Msp I Al. The results of this studyindicate that the haplotype approach to the identification ofp53 germ line alleles associated with increased susceptibilityto cancer is far more powerful than the analysis of single polymorphisms,since the capacity to identify germ line alleles predisposingto cancer should increase with the number of polymorphic sitesincluded in the analysis.     

Germline mutations in the neurofibromatosis type 2 tumour suppressor gene

The recent identification of the NF2 tumour suppressor genehas enabled large scale screening for pathological mutationsin the gene. We have sought germline mutations In the NF2 geneby SSCP and heteroduplex analysis of cDNA and genomic DNA samplesfollowed by cloning and sequencing of mutant alleles. In thepresent report we describe 11 putative pathological mutations,including five nonsense mutations, three short insertions ordeletions cauing frameshifts and three missense mutations. Moststop mutations and frameshift mutations were found In Individualsexpressing a severe phenotype while one of the three missensemutations was associated with a mild phenotype. Four unrelatedNF2 patients of the 93 tested were found to have identical nonsensemutations caused by a C to T transition (C169) in a CpG dinucleotide,which is a potential mutational hotspot in the NF2 tumour suppressorgene.     

Scleromyxoedema with features of systemic sclerosis.

The case is described of a patient with scleromyxoedema with features typical of systemic sclerosis. The features were so characteristic that the disease was misdiagnosed as systemic sclerosis. A brief review of the association of the two diseases is given.     

No evidence for association between the −112G/A polymorphism of UGRP1 and childhood atopic asthma

BACKGROUND: Susceptibility to asthma is known to involve genetic factors. Genome-wide screens have indicated that the chromosome 5q31-q34 region is linked to and/or associated with asthma. A new gene, named UGRP1 and reported by Niimi et al., encodes uteroglobin-related protein and is expressed in the lung and trachea. Niimi et al. showed the -112G/A polymorphism of the UGRP1 gene to be associated with asthma in a case-control study. OBJECTIVE: The objective of the present study was to replicate this association and confirm the possible role of the UGRP1-112G/A polymorphism in the aetiology of childhood asthma in a Japanese population. METHODS AND RESULTS: We conducted a transmission disequilibrium test (TDT) in 131 families identified through paediatric patients being treated for asthma. A case-control study was also carried out by comparing the probands and 137 unrelated non-atopic non-asthmatic Japanese children and 211 unrelated healthy Japanese adults. The -112G/A polymorphism was genotyped by the PCR-RFLP method. The TDT revealed that the -112A allele was not preferentially transmitted to asthma-affected children (P=0.85). Neither the presence of at least one A allele in an individual's genotype (sum of the G/A and A/A genotypes) nor the -112A allele was more prevalent among the asthma subjects than among the control subjects. CONCLUSION: Our findings indicate that the UGRP1-112G/A polymorphism does not play a substantial role in genetic predisposition to childhood asthma in this Japanese population.     

Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse

Cyclic nucleotides are important second messengers that mediate a number of cellular responses to external signals. Cyclic nucleotide phosphodiesterases play a role in signal transduction by regulating the cellular concentrations of these messengers. Here, we have applied Southern analyses of somatic cell hybrid lines and of recombinant inbred (RI) mouse strains as well as fluorescence chromosomal in situ hybridization (FISH) to chromosomally localize five cAMP-specific nucleotide phosphodiesterase genes in human and mouse. GenesDPDE1, DPDE2, DPDE3, andDPDE4 that share sequence homology with theDrosophila dunce gene were assigned to human chromosomes 19 (DPDE1 andDPDE2), 5q12 (DPDE3), and 1p31 (DPDE4) and to mouse chromosomes 8, 9, 13, and 4, respectively. The high-affinity cAMP-specific phosphodiesterase gene (HCP1) was mapped to human chromosome 8q13-q22. Since these genes are potential candidates for involvement in psychiatric or behavioral disorders, knowledge of their chromosomal localizations will facilitate the discovery of their association with disease genes as they are being mapped by linkage studies.     

Infantile autism—fragile X: Molecular findings support genetic heterogeneity

Twenty-two members of 18 families with autism have been examined for the presence of mutations and abnormal methylation in the FMR-1 region at Xq27.3. All patients fulfilled diagnostic criteria of infantile autism. A characteristic pattern of insertion and methylation were detected after Southern blot analysis in 7 autistic individuals expressing the fragile site at Xq27.3. Normal DNA patterns were observed in 15 autistic boys cytogenetically negative for the fragile site. The results indicate a lack of involvement of the FMR-1 region in infantile autists negative for fragile X expression. © 1992 Wiley-Liss, Inc.     

UK clinicians'' knowledge of and attitudes to the prenatal diagnosis of single gene disorders.

Postal questionnaires were sent to 308 clinicians in the UK (general practitioners, obstetricians, clinical geneticists, neurologists, paediatricians, and paediatric neurologists) to assess their knowledge of, and attitudes to, the prenatal diagnosis of three common single gene disorders, Huntington's disease (HD), cystic fibrosis (CF), and Duchenne muscular dystrophy (DMD). Replies received numbered 213, a response rate of 69%. Overall, 95% of responding clinicians thought that offering prenatal diagnosis for the three test conditions was often or always appropriate. There was a correlation between the clinicians' estimates of life expectancy and their willingness to offer prenatal diagnosis (p less than 0.01). Among the non-geneticists questioned, fewer than 50% of general practitioners answered correctly regarding the availability of prenatal tests.     

Ignoring Distant Genealogic Loops Leads to False-positives in Homozygosity Mapping

Distant consanguineous loops are often unknown or ignored during homozygosity mapping analysis. This may potentially lead to an increased rate of false-positive linkage results. We show that failure to take into account the distant loops may seriously underestimate the degree of consanguinity, especially for people from genetically isolated populations; in 6 Alzheimer's disease (AD) patients the distant loops accounted for 57.7 % of inbreeding on average. Theoretical evaluation showed that ignoring distant loops, which account for 18-75% of inbreeding, inflates the frequency of false positive conclusions substantially in 2-point linkage analysis, up to several hundred times. In multipoint linkage analysis of the 6 AD patients a chromosome-wide "empirical" significance of 5% corresponded to a true false positive rate of 11.1%. We show that converting multiple loops to a hypothetical loop capturing all inbreeding may be a convenient solution to avoid false positive results. When extended genealogic data are not available a hypothetical loop may still be constructed based on genomic data.