title: Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss.
abstract: We report on an autosomal-recessive variant of Ehlers-Danlos syndrome (EDS) characterized by severe muscle hypotonia at birth, progressive scoliosis, joint hypermobility, hyperelastic skin, myopathy, sensorineural hearing impairment, and normal pyridinoline excretion in urine. Clinically, the disorder shares many features with the kyphoscoliotic type of EDS (EDS VIA) and Ullrich congenital muscular dystrophy. Linkage analysis in a large Tyrolean kindred identified a homozygous frameshift mutation in FKBP14 in two affected individuals. Based on the cardinal clinical characteristics of the disorder, four additional individuals originating from different European countries were identified who carried either homozygous or compound heterozygous mutations in FKBP14. FKBP14 belongs to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases). ER-resident FKBPs have been suggested to act as folding catalysts by accelerating cis-trans isomerization of peptidyl-prolyl bonds and to act occasionally also as chaperones. We demonstrate that FKBP14 is localized in the endoplasmic reticulum (ER) and that deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo. Furthermore, indirect immunofluorescence of FKBP14-deficient fibroblasts indicated an altered assembly of the extracellular matrix in vitro. These findings suggest that a disturbance of protein folding in the ER affecting one or more components of the extracellular matrix might cause the generalized connective tissue involvement in this disorder. FKBP14 mutation analysis should be considered in all individuals with apparent kyphoscoliotic type of EDS and normal urinary pyridinoline excretion, in particular in conjunction with sensorineural hearing impairment.
authors.affiliation: Department of Paediatrics IV - Neonatology, Paediatric Neurology and Inherited Metabolic Disorders, Innsbruck Medical University, Austria. matthias.baumann@uki.at
authors.forename: Matthias
authors.initials: M
authors.lastname: Baumann
authors.forename: Cecilia
authors.initials: C
authors.lastname: Giunta
authors.forename: Birgit
authors.initials: B
authors.lastname: Krabichler
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Zoppi
authors.forename: Marina
authors.initials: M
authors.lastname: Colombi
authors.forename: Reginald E
authors.initials: RE
authors.lastname: Bittner
authors.forename: Susana
authors.initials: S
authors.lastname: Quijano-Roy
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schreiber
authors.forename: Yaqun
authors.initials: Y
authors.lastname: Zou
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Norma Beatriz
authors.initials: NB
authors.lastname: Romero
authors.forename: Robert Yves
authors.initials: RY
authors.lastname: Carlier
authors.forename: Albert
authors.initials: A
authors.lastname: Amberger
authors.forename: Andrea
authors.initials: A
authors.lastname: Deutschmann
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Marianne
authors.initials: M
authors.lastname: Rohrbach
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
authors.forename: Kevin
authors.initials: K
authors.lastname: Rostásy
authors.forename: Daniela
authors.initials: D
authors.lastname: Karall
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Christine
authors.initials: C
authors.lastname: Fauth
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000596:Amino Acids / Q000652:urine; D002648:Child; D002675:Child, Preschool; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000652:urine; D004721:Endoplasmic Reticulum / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D016368:Frameshift Mutation; D014644:Genetic Variation; D034381:Hearing Loss / Q000235:genetics* / Q000652:urine; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D019696:Peptidylprolyl Isomerase / Q000235:genetics*; D010641:Phenotype; D017510:Protein Folding; D019745:cis-trans-Isomerases / Q000235:genetics
chemical_list: D000596:Amino Acids; C015484:pyridinoline; D019745:cis-trans-Isomerases; C572897:FKBP14 protein, human; D019696:Peptidylprolyl Isomerase