Ullrich syndrome is a recessive congenital muscular dystrophy affecting connective tissue and muscle. The molecular basis is unknown. Reverse transcription-PCR amplification performed on RNA extracted from fibroblasts or muscle of three Ullrich patients followed by heteroduplex analysis displayed heteroduplexes in one of the three genes coding for collagen type VI (COL6). In patient A, we detected a homozygous insertion of a C leading to a premature termination codon in the triple-helical domain of COL6A2 mRNA. Both healthy consanguineous parents were carriers. In patient B, we found a deletion of 28 nucleotides because of an A --> G substitution at nucleotide -2 of intron 17 causing the activation of a cryptic acceptor site inside exon 18. The second mutation was an exon skipping because of a G --> A substitution at nucleotide -1 of intron 23. Both mutations are present in an affected brother. The first mutation is also present in the healthy mother, whereas the second mutation is carried by their healthy father. In patient C, we found only one mutation so far-the same deletion of 28 nucleotides found in patient B. In this case, it was a de novo mutation, as it is absent in her parents. mRNA and protein analysis of patient B showed very low amounts of COL6A2 mRNA and of COL6. A near total absence of COL6 was demonstrated by immunofluorescence in fibroblasts and muscle. Our results demonstrate that Ullrich syndrome is caused by recessive mutations leading to a severe reduction of COL6.

Italian (Calabria) 96 43 .448 ‫ע‬ .051 Spanish a 66 36 .545 ‫ע‬ .061 Sub-Saharan African: Dendi 24 0 0 Bariba 26 2 .077 ‫ע‬ .052 Berba 32 3 .094 ‫ע‬ .051 Fon 96 8 .083 ‫ע‬ .028 Total b 178 13 .073 ‫ע‬ .019 Asian: Tharu a 108 21 .194 ‫ע‬ .038 Chinese a 24 9 .375 ‫ע‬ .099 Indonesian 98 2 .020 ‫ע‬ .014 Amerindian: Cayapa a 114 49 .430 ‫ע‬ .046 Mixed: Ethiopian: Amhara 54 4 .074 ‫ע‬ .033 Oromo 54 3 .055 ‫ע‬ .031 Total b 108 7 .065 ‫ע‬ .024 African Ecuadoran: Viche a 82 13 .183 ‫ע‬ .043 a Testable population, except for Calabrians (Italy), in Hardy-Weinberg equilibrium. b Populations were pooled when compatibility was verified by a x 2 test of heterogeneity.

SummaryA difference in the prevalence of venous thromboembolism (TE) in major human groups has been described and an uneven distribution of FV Leiden mutation over the world has recently been reported.We investigated FV Leiden mutation in 584 apparently healthy sub#jects mostly from populations different from those previously investi#gated: 170 Europeans (Spanish, Italians), 101 sub-saharan Africans (Fon, Bariba, Berba, Dendi), 115 Asians (Indonesians, Chinese, Tharus), 57 Amerindians (Cayapa), 84 Afroamericans (Rio Cayapa, Viche), and 57 Ethiopians (Amhara, Oromo).The mutation was detected in only 1/115 Asian (Tharu) and in 5/170 Europeans (4 Italians, 1 Spanish).These data confirm that in non-Europeans the prevalence of FV mutation is at least 7 times lower than in Europeans and provide indirect evidence of a low prevalence not only of the FV Leiden gene but also of other genes leading to more severe thrombophilia. Finally, findings from the literature together with those pertaining to this study clearly show a marked heterogeneity among Europeans.

The clustering of the mutations in a relatively narrow area of the three collagen type VI chains in patients with Bethlem myopathy (BM) suggests that mutations in different regions could result in different phenotypes or in no phenotype at all. Moreover, the detection of mutations in only 60% of the patients suggests the existence of at least another gene associated with BM. The authors propose the direct sequencing of COL6 cDNAs as the first mutation screening analysis in BM, given the high number of exon-skipping events.