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: Matthias Baumann, Cecilia Giunta, Birgit Krabichler, Franz Rüschendorf, Nicoletta Zoppi, Marina Colombi, Reginald E Bittner, Susana Quijano-Roy, Francesco Muntoni, Sebahattin Cirak, Gudrun Schreiber, Yaqun Zou, Ying Hu, Norma Beatriz Romero, Robert Yves Carlier, Albert Amberger, Andrea Deutschmann, Volker Straub, Marianne Rohrbach, Beat Steinmann, Kevin Rostásy, Daniela Karall, Carsten G Bönnemann, Johannes Zschocke, Christine Fauth
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 90 Issue 2 Pg. 201-16 (Feb 10 2012) ISSN: 1537-6605 [Electronic] United States
• PMID: 22265013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• pyridinoline
• cis-trans-Isomerases
• FKBP14 protein, human
• Peptidylprolyl Isomerase

Topics

• Abnormalities, Multiple (genetics)
• Adolescent
• Amino Acids (urine)
• Child
• Child, Preschool
• Ehlers-Danlos Syndrome (genetics, urine)
• Endoplasmic Reticulum (genetics)
• Extracellular Matrix (genetics)
• Female
• Fibroblasts (metabolism)
• Frameshift Mutation
• Genetic Variation
• Hearing Loss (genetics, urine)
• Heterozygote
• Homozygote
• Humans
• Male
• Middle Aged
• Peptidylprolyl Isomerase (genetics)
• Phenotype
• Protein Folding
• cis-trans-Isomerases (genetics)