A PATIENT WITH EHLERS-DANLOS SYNDROME TYPE-VI IS A COMPOUND HETEROZYGOTE FOR MUTATIONS IN THE LYSYL HYDROXYLASE GENE

In the present study, we have isolated and sequenced the complementary DNAs of two mutant alleles for lysyl hydrosylase (LH) in fibroblasts from one patient (AT750) with Ehlers-Danlos syndrome type VI (EDS VI). We have identified a putative mutation in each allele which may be re sponsible for the patient's decreased LH (normalized to prolyl hydroxy lase) activity (24% of normal). Intermediate levels of LH activity wer e measured in the patient's parents, who are clinically normal (father 52%; mother 86%). After the cloning of cDNAs and amplification by PCR , sequence analysis revealed two equally distributed populations of cD NAs for LH in the AT750 cell line. Each allele revealed different but significant changes from the normal sequence. In one allele (allele 1) , the most striking change was a triple base deletion that would resul t in the loss of residue Glu(532). The most significant difference in the other allele (allele 2) was a G --> A change which would produce a Gly(678) --> Arg codon change in a highly conserved region of the enz yme. Restriction analysis identified that allele 1 was inherited from the proband's mother and allele 2 from the father. This study represen ts the first example of compound heterozygosity for the LH gene in an EDS VI patient, and it appears that there is an additive effect of eac h mutant allele on clinical expression in this patient.