Ar

Type V procollagen

Not known Type III procollagen

Lysyl hydroxylase-1

COL5Al/COL5A2

Not known COL3Al

PLODl

Type I procollagen

Methods for laboratory diagnosis

COLlAl/COLlA2

Partial loss or complete skipping of exon 6

Procollagen-N-proteinase ADAMTS-2 gene

COL5A1 ''null-allele'' testing

Molecular screening for mutations in COL5A1 or COL5A2 Not available

Biochemical analysis of type III collagen by SDS-PAGE

Molecular screening for mutations in COL3A1 Increased ratio deoxypyridoline to pyridoline cross-links in urine by HPLC Measurement of lysyl hydroxylase-1 activity Molecular screening of PLOD1 gene Biochemical analysis of type I collagen by SDS-PAGE Detection of complete or partial skipping of exon 6 in COL1A1 or COL1A2 Biochemical analysis of type I collagen by SDS-PAGE Molecular screening of ADAMTS-2-gene distributed in a variety of tissues. In skin, tendon, and bone it is present mainly as [a1(V)]2 a2(V) heterotrimers. Type V collagen forms heterotypic fibrils with type I collagen and regulates the diameter of those fibrils.[4] It is thought that the huge amino-terminal propeptide of type V collagen is responsible for this regulatory function.

Biochemical studies on cultured fibroblasts, performed by sodium dodecyl sulfate-polyacrylamide gel electro-phoresis (SDS-PAGE) of metabolically labeled collagens produced by dermal fibroblasts, are usually not useful in confirming the diagnosis because type V collagen is synthesized by fibroblasts at low levels, so that quantita-tion and evaluation of alterations in electrophoretic mobility are poorly reproducible. Rarely, an abnormal electrophoretic pattern for type I collagen is detected because of nonglycine substitution (R134C) in the COL1A1 gene coding for the proal(I) collagen chain of type I collagen.[5] A COL5A1 ''null-allele'' test is available for clinical testing. This test detects a nonfunctional COL5A1 allele by genotyping polymorphic markers at the genomic and the cDNA level, hence requiring cultured fibroblasts. This test detects a COL5A1 null-allele in approximately 30% of individuals with classic EDS. Sequence analysis of the COL5A1 and the COL5A2 gene is available on research basis only. Approximately 50% of patients with classic EDS have an identifiable mutation in one of these genes. Most molecular defects identified for classic EDS lead to haploinsufficiency of the COL5A1 mRNA. In approximately one-third of classic EDS patients, nonsense, frameshift, or splice site mutations that introduce a premature termination codon are responsible for a nonfunctional COL5A1 allele.[6,7] Several mechanisms lead to nonsense-mediated decay of the mutation-bearing mRNA or to failure of the chains to associate. The predicted consequence is synthesis of about half the amount of normal type V collagen. Structural mutations in the COL5A1 and the COL5A2 gene, which exert a dominant negative effect, have been demonstrated in approximately 15-20 patients with classic EDS. These structural mutations are most commonly splice site mutations leading to exon skipping, and remarkably few point mutations that result in the substitution of a glycine in the triple-helical region of the collagen molecule by a bulkier amino acid. A unique point mutation in the COL5A1 gene that changes a highly conserved cysteine residue to a serine in the C-terminal propeptide of the a1(V) collagen chain has also been identified.[8] A G530S substitution located in the amino-terminal propeptide of the a1(V) collagen chain may be disease modifying in the heterozygous state and disease causing in the homozygous state.[9,10]

Recently, mutations in a noncollagenous protein, tenascin X, have been demonstrated to cause an autosomal recessive condition with great similarity to classic EDS, including hyperextensible skin, hypermobile joints, and easy bruising, but without delayed wound healing or atrophic scarring.[11]

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