Jean Rey

CpG dinucleotides are mutation hot spots in phenylketonuria.

The coding region of the phenylalanine hydroxylase (PAH) gene contains 22 CpG dinucleotides, including five doublets in the seventh exon of the gene. We hypothesized that CpG doublets could represent mutation hot spots in PAH deficiencies and we carried out the systematic sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of two novel missense mutations whose location and nature (CG to CA and CG to TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet (codon 261arg----gln and codon 252arg----trp). Moreover, the codon 261 mutation was found to be associated with mutant restriction fragment length polymorphism (RFLP) haplotype 1, the most frequent mutant RFLP haplotype at the PAH locus in the studies reported thus far. However, since the mutation was detected in only 36% of haplotype 1 mutant alleles, it appears that this haplotype at the PAH locus is genotypically heterogeneous in Mediterranean countries.

Spectrum of phenylketonuria mutations in Western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus

SummaryA total of 252 chromosomes from 126 patients with phenylalanine hydroxylase (PAH) deficiencies were analyzed for both mutant genotypes and restriction fragment length polymorphism (RFLP) haplotypes at the PAH locus. The mutant genes studied originated either from Western Europe (116 alleles) or from Mediterranean countries (136 alleles). Only 27% of all mutant alleles were found to carry identified mutations, particularly mutations at codon 252 (2.3%), 261 (7.5%), 280 (6.3%), 408 (3.5%) and at the splice donor site of intron 12 (6.3%). The mutant genotypes were associated with RFLP haplotypes 7, 1, 38, 2 and 3 at the PAH locus respectively. Except for the splice mutation of intron 12, these associations were preferential, but not exclusive, since the other four mutations were found on the background of at least two RFLP haplotypes. These results, together with the observation that 85% of PAH deficient patients are heterozygotes for their mutant genotypes, emphasize the great heterogeneity of PAH deficiencies in Mediterranean countries and hamper systematic DNA testing for carrier status in this population.

Maple syrup urine disease: two different forms within a single family

SummaryA family is reported in which the index case presented with an acute form of maple syrup urine disease (MSUD), whereas two of her sisters and her father were found to have an almost asymptomatic form of the disease. It is proposed that the members of this family are compound heterozygotes for the classical deficient mutant gene and for a “variant” allele.

Genetics of disorders of intestinal digestion and absorption.

In this review we shall deal with the problems of intestinal absorption, taken in a broad sense, and its disorders. These problems will be considered according to the location of the primary disturbance, i.e., the pancreas or the gut, and to the nutrients which are affected, leading either to generalized or to specific malabsorptions.