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Bone Abstracts (2014) 3 CC3 | DOI: 10.1530/boneabs.3.CC3

ECTS2014 Clinical Case Oral Communications (1) (4 abstracts)

Absence of ER cation channel TMEM38B/TRIC-B causes recessive osteogenesis imperfecta by dysregulation of collagen post-translational modification

Wayne Cabral 1 , Elena Makareeva 2 , Masaki Ishikawa 3 , Aileen Barnes 1 , MaryAnn Weis 4 , Felicitas Lacbawan 5 , David Eyre 4 , Yoshihiko Yamada 3 , Sergey Leikin 2 & Joan Marini 1


1Bone and Extracellular Matrix Branch, NICH, NIH, Bethesda, Maryland, USA; 2Section on Physical Biochemistry, NICHD, NIH, Bethesda, Maryland, USA; 3Molecular Biology Section, NIDCR, NIH, Bethesda, Maryland, USA; 4Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, Washington, USA; 5Department of Medical Genetics, Children’s National Medical Center, Washington, District of Columbia, USA.

Recessive osteogenesis imperfecta (OI) is caused by mutations in genes encoding proteins involved in post-translational interactions with type I collagen. A founder mutation in a new gene responsible for recessive OI has recently been reported in Bedouins from Israel and Saudi Arabia, who have a homozygous deletion of TMEM38B exon 4 and surrounding intronic sequence. TMEM38B encodes TRIC-B, an integral ER membrane monovalent cation channel involved in Ca++ release from intracellular stores. However, the molecular mechanisms through which this mutation causes an OI phenotype are unknown. We identified a 20 month-old girl with moderately severe OI, born to consanguineous parents from Saudi Arabia, who is homozygous for the TMEM38B founder mutation. TMEM38B transcripts are 25% of control level, and include six alternatively spliced forms of the transcript, of which one in-frame transcript deletes the central transmembrane domain and putative ion pore. The complete absence of TRIC-B protein was confirmed by Western blot and resulted in decreased intracellular Ca++ concentration and ATP-induced Ca++ flux from the ER. Surprisingly, SDS-Urea PAGE demonstrated increased electrophoretic migration of collagen alpha chains, suggesting altered post-translational modification. Although LH1 transcripts and protein were increased, proband collagen revealed a 30% reduction in helical lysine hydroxylation. Furthermore, the detection of lower stability collagen species (30–40% of total collagen) on differential scanning calorimetry, increased intracellular PDI and GRP/BiP, and decreased procollagen pericellular processing, imply that proband procollagen conformation is abnormal. FKBP65, which is stabilized by Ca++ and required for collagen telopeptidyl hydroxylation and crosslinking, was decreased in proband fibroblasts. Matrix deposited in culture by proband fibroblasts has 30% reduction of immaturely and maturely crosslinked collagen. We propose that these data support a role for TRIC-B in intracellular Ca++ mobilization, and that absence of TRIC-B causes OI by dysregulation of multiple Ca++-regulated collagen-specific chaperones and modifying enzymes in the ER.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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