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The SFTPB gene indel g.1549C > GAA (121ins2) accounts for about 2/3 of the mutant alleles underlying complete surfactant protein B deficiency. It is unclear, however, whether its prevalence is due to recurrent mutation or a founder effect. The underlying mutational mechanism was therefore sought through the analysis of local DNA sequence complexity. A relatively complex two-step process was proposed: the first step involving slipped mispairing mediated by a direct repeat and generating an AGAA micro-insertion, the second step involving hairpin loop resolution resulting in a CA micro-deletion. The possibility of a founder effect was then assessed by typing 8 intragenic SNPs in 17 independent 121ins2 chromosomes from 10 probands, with parental non-121ins2 chromosomes serving as controls. The 121ins2 chromosomes were assigned to three discrete haplotypes, whilst control chromosomes were distributed between 10 of the 11 observed parental haplotypes. The 121ins2 mutation was in strong and significant linkage disequilibrium (LD) with the tightly linked marker g.1580T/C (|D'| = 1; P approximately 0.024), although only moderate LD was found with the rest of the locus (|D'| approximately 0.54; P approximately 0.136). Data on haplotype structure and the locus LD pattern, obtained from 81 independent Western-European chromosomes, were consistent with the three mutation-bearing haplotypes having originated from a common ancestor by recombination. Interestingly, all families harboring the 121ins2 indel had ancestors from a region of Northwestern Europe populated by Frankish/Saxon migration. Taken together, these data are consistent with the view that an indel mutation occurred on a relatively common SFTPB haplotype and now accounts for the majority of (and possibly all) extant 121ins2 chromosomes., ((c) 2005 Wiley-Liss, Inc.)

Chronic distal spinal muscular atrophy (Chronic DSMA, MIM (*)607088) is a rare autosomal recessive disorder characterized by a progressive motor weakness and muscular atrophy, predominating in the distal parts of the limbs. A form of Chronic DSMA gene has been previously mapped to chromosome 11q13 in the 10.3 cM interval defined by loci D11S1889 and D11S1321. By linkage analysis in 12 European Chronic DSMA families, we showed that a disease gene maps to chromosome 11q13.3 (Z(max)=6.66 at theta=0.00 at the DSM4 locus) and suggested that this condition is genetically homogeneous. Recombination events allowed us to reduce the genetic interval to a 2.6 cM region, telomeric to the IGHMBP2 gene, excluding this gene as the disease causing gene in Chronic DSMA. Moreover, partial linkage disequilibrium was found between three rare alleles at loci D11S1369, DSM4 and D11S4184 and the mutant chromosome in European patients. Analysis of the markers at these loci strongly suggests that most Chronic DSMA chromosomes are derived from a single ancestor. Refinement of the Chronic DSMA locus will hopefully allow to test candidate genes and lead to identification of the disease-causing mutations.

A 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.

Geographical variation in the incidence of an Anencephaly and Spina-Bifida is well documented. The highest rates for these malformations were found in Ireland, Wales, Scotland and in Western regions of England. These rates decrease progressively towards eastern Europe. In France the highest rates were found in some regions of Brittany. The geographical correlations between the mortality rates of Spina-Bifida and incidence of Spina-Bifida and Anencephaly and the HLA antigen frequencies are studied. There is a positive correlation with A1 and B8 and a negative one with B5 and BW35. The role of the HLA system in these associations is discussed.

The geographical correlation between the incidence of spina bifida and anencephaly and the HLA and ABO antigen frequencies are studied. There is a positive correlation between these malformations and A1 and B8, and a negative correlation with B5 and Bw35. The role of the HLA system itself, or of a human T-like locus, is discussed. This study provides evidence of a possible genetic background of susceptibility to these malformations.

It is suggested that the observed difference in duration of pregnancy between Blacks and Whites is partly physiological since it is not entirely explained by social inequities alone. This study compares women with well-defined gestational periods seeking attention at the Antoine Béclère Maternity Clinic. Group A consists of French women of European ancestry, Group B, those born in the French Antilles of mixed ancestry, and Group C black African women with insignificant European admixture. When compared to Group A, within each socio-economic class, group B and C have shorter gestational periods. These differences persist after adjustment for socio-economic variables, so that other explanations should be considered, specifically genetic determinants.

The geographical correlations between the incidence of various cancers and the HLA and ABO antigen frequencies are studied. There is, for example, a positive correlation between breast and colorectal carcinoma and AI, B8 and B12 antigens, and a negative one between prostate carcinoma and B12. The role of the HLA system itself or other genes involved in these associations is discussed. This study gives some evidence of a possible genetic background of susceptibility or resistance to cancer.