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The type VI variant of the Ehlers-Danlos syndrome (EDS) is a recessively inherited connective tissue disorder which, in most families, is due to a deficiency in lysyl hydroxylase activity. We have recently characterized a homozygous duplication of 8.9 kb in the lysyl hydroxylase gene (PLOD) in two EDS VI families. The duplication is caused by a homologous recombination of Alu sequences in introns 9 and 16. Using PCR, we have analyzed 26 additional EDS VI families from various countries and found that 7 of them have this duplication. Our data has shown a frequency of 19.1% for this mutant allele among 35 EDS VI families studied by us so far. Our haplotype analysis shows a variation in the sequence of DNA region surrounding the duplication. There is an association between a particular allele size class, the long form, at the dinucleotide repeat within intron 16 and the duplication mutation in PLOD. Screening of a general population revealed one positive finding among 582 alleles tested. An abnormal sequence in exon 17 of the gene, which generated a stop codon in the exon sequence and aberrant mRNA processing, was responsible for the nonfunctionality of the other allele in one of the compound heterozygous patients.

Objective and Background: To find an explanation at the molecular level for the high prevalence of myotonia congenita in northern Finland and the exceptional pattern of inheritance of the disease in many families, and to study genotype-phenotype correlation in the patients. Methods: Forty-six patients with myotonia congenita and 16 unaffected relatives from 24 families were studied. All 23 exons and their flanking regions of the gene for the chloride channel protein ( ClC-1 ) were sequenced from at least one patient from all families. Results: There were three different mutations of ClC-1 in the patients: one in exon 11, a T-to-G transversion that resulted in the substitution of cysteine for phenylalanine at amino acid position 413 (F413C); one in exon 15, a C-to-T transition that resulted in the substitution of valine for alanine at amino acid position 531 (A531V); and one in exon 23, a C-to-T transition that resulted in the substitution of a stop codon for an arginine codon at amino acid position 894 (R894X). Conclusions: Molecular studies showed that even in families with apparent dominant inheritance, the actual mode of inheritance was autosomal recessive. This was explained not only by the observed consanguinity in some families but by an enrichment of three different mutations of the ClC-1 gene and a consequent high number of compound heterozygotes in the population. One of the mutations is unique to northern Finland. The conspicuous enrichment of the mutations is likely due to the founder effect and isolation by distance, as in other diseases in the Finnish heritage.