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

The Ehlers-Danlos syndromes are a heterogeneous group of inherited connecti ve tissue disorders that are characterized by joint hypermobility and skin fragility and hyperextensibility. Patients with the autosomal recessive typ e VI variant of the Ehlers-Danlos syndromes (EDS VI), also classified as th e kyphoscoliotic type, are clinically characterized by neonatal kyphoscolio sis, 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 collag en biosynthesis. This enzyme hydroxylates specific lysine residues in the c ollagen 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 col lagen its tensile strength. At least 20 different mutations have been ident ified in the LH1 gene (the originally described form) that contribute to LH deficiency and the clinical characteristics of EDS VI. Two of these mutati ons, a large duplication of exons 10-16, arising from a homologous recombin ation 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. Alte rnative processing pathways involving alternate splicing and mRNA degradati on, which reduce the effect of the mutant allele and restore partial activi ty of the enzyme, have been identified. A second class of EDS VI has been p roposed in which patients have the clinical phenotype of EDS VI but their l evels of LH activity are normal. The biochemical basis for this form of EDS VI is currently unknown. (C) 2000 Academic Press.