Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI.

The Ehlers-Danlos syndromes are a heterogeneous group of inherited connective tissue disorders that are characterized by joint hypermobility and skin fragility and hyperextensibility. Patients with the autosomal recessive type VI variant of the Ehlers-Danlos syndromes (EDS VI), also classified as the kyphoscoliotic type, are clinically characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth. Biochemically, this has been attributed to a deficiency of lysyl hydroxylase (LH), an important posttranslational modifying enzyme in collagen biosynthesis. This enzyme hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines which have two important functions. The residues serve as attachment sites for galactose and glucosylgalactose and they also act as precursors of the crosslinking process that gives collagen its tensile strength. At least 20 different mutations have been identified in the LH1 gene (the originally described form) that contribute to LH deficiency and the clinical characteristics of EDS VI. Two of these mutations, a large duplication of exons 10-16, arising from a homologous recombination of intronic Alu sequences, and a nonsense mutation, Y511X, in exon 14 of the LH1 gene, have been identified in five or more unrelated patients. Both mutations appear to have originated from a single ancestral gene. Alternative processing pathways involving alternate splicing and mRNA degradation, which reduce the effect of the mutant allele and restore partial activity of the enzyme, have been identified. A second class of EDS VI has been proposed in which patients have the clinical phenotype of EDS VI but their levels of LH activity are normal. The biochemical basis for this form of EDS VI is currently unknown.