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K uskokwim Syndrome, a Recessive Congenital Contracture Disorder, Extends the Phenotype of FKBP10 Mutations
Author(s) -
Barnes Aileen M.,
Duncan Geraldine,
Weis MaryAnn,
Paton William,
Cabral Wayne A.,
Mertz Edward L.,
Makareeva Elena,
Gambello Michael J.,
Lacbawan Felicitas L.,
Leikin Sergey,
Fertala Andrzej,
Eyre David R.,
Bale Sherri J.,
Marini Joan C.
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22362
Subject(s) - missense mutation , genetics , biology , arthrogryposis , muscle contracture , phenotype , microbiology and biotechnology , gene , anatomy
ABSTRACT Recessive mutations in FKBP10 at 17q21.2, encoding FKBP 65, cause both osteogenesis imperfecta ( OI ) and B ruck syndrome ( OI plus congenital contractures). Contractures are a variable manifestation of null/missense FKBP10 mutations. K uskokwim syndrome ( KS ) is an autosomal recessive congenital contracture disorder found among Y up'ik E skimos. Linkage mapping of KS to chromosome 17q21, together with contractures as a feature of FKBP10 mutations, made FKBP10 a candidate gene. We identified a homozygous three‐nucleotide deletion in FKBP10 (c.877_879del TAC ) in multiple K uskokwim pedigrees; 3% of regional controls are carriers. The mutation deletes the highly conserved p. T yr293 residue in FKBP 65's third peptidyl‐prolyl cis – trans isomerase domain. FKBP10 transcripts are normal, but mutant FKBP 65 is destabilized to a residual 5%. Collagen synthesized by KS fibroblasts has substantially decreased hydroxylation of the telopeptide lysine crucial for collagen cross‐linking, with 2%–10% hydroxylation in probands versus 60% in controls. Matrix deposited by KS fibroblasts has marked reduction in maturely cross‐linked collagen. KS collagen is disorganized in matrix, and fibrils formed in vitro had subtle loosening of monomer packing. Our results imply that FKBP10 mutations affect collagen indirectly, by ablating FKBP 65 support for collagen telopeptide hydroxylation by lysyl hydroxylase 2, thus decreasing collagen cross‐links in tendon and bone matrix. FKBP10 mutations may also underlie other arthrogryposis syndromes.