Hum Hered

Identification of two novel mutations in the hydroxymethylbilane synthase gene in three patients from two unrelated families with acute intermittent porphyria.

Ong PM. Lanyon WG. Hift RJ. Halkett J. Cramp CE. Moore MR. Connor JM.
Duncan Guthrie Institute of Medical Genetics, Yorkhill, Glasgow, UK. cypo@musica.mcgill.ca
We have screened the hydroxymethylbilane synthase cDNAs of 3 patients from 2 families suffering from acute intermittent porphyria (AIP) from Scotland and South Africa using heteroduplex and chemical cleavage of mismatch analyses. Direct sequencing was used to characterise the mutations. The two novel mutations identified were a missense mutation at nucleotide position 64 in exon 3 (R22C) and a single base-pair deletion in exon 15. These mutations are predicted to affect the normal function of the enzyme and, therefore, are expected to be the primary cause of disease in these patients.

A novel missense mutation in the DNA mismatch repair gene hMLH1 present among East Asians but not among Europeans.

Year 1998
Wang Y. Friedl W. Lamberti C. Nothen MM. Kruse R. Propping P.
Institute of Human Genetics, University of Bonn, Germany.
In a search for germline mutations in the DNA mismatch repair genes hMSH2 and hMLH1 in Chinese patients with colorectal cancer we identified a novel missense mutation (V384D) in exon 12 of the hMLH1 gene in 4 out of 26 individuals. This mutation had not been observed in any of 109 German patients who either fulfill the clinical criteria of hereditary nonpolyposis colorectal cancer or had developed colorectal cancer at an early age. In a second series of experiments, DNA samples of 80 healthy. Japanese and 100 healthy Germans were examined for the presence of the V384D mutation. It was observed in 4 Japanese, but in none of the German individuals. Thus, the V384D mutation seems to be confined to the East-Asian population. Since this missense mutation occurs at a less conserved region of the hMLH1 gene, it may represent a nonfunctional polymorphism. However, a role in the pathogenesis of colorectal cancer cannot be ruled out from the present study.

Phenotypic variability in five cystic fibrosis patients compound heterozygous for the Y1092X mutation.

Year 1998
De Braekeleer M. Allard C. Leblanc JP. Simard F. Aubin G.
Departement des Sciences Humaines, Universite du Quebec a Chicoutimi, Hopital de Chicoutimi, Canada.
Five cystic fibrosis (CF) patients distributed in three families and compound heterozygotes for the Y1092X mutation have been followed for a period ranging from 5 to 20 years. The genealogical reconstruction identified a common ancestor couple to all 3 families at the 5th generation. All 5 patients were pancreatic insufficient. A high variability in the clinical aspects and pulmonary function was seen between the families, but not within. Based on our observations, it will be very difficult to predict the course of disease for CF patients with the Y1092X mutation, even if they are closely related (first-degree cousins).