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A Deletion Mutation in TMEM38B Associated with Autosomal Recessive Osteogenesis Imperfecta

Authors

  • Michael Volodarsky,

    1. The Morris Kahn Laboratory of Human Genetics at the National Institute for Biotechnology in the Negev (NIBN) and Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel
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  • Barak Markus,

    1. The Morris Kahn Laboratory of Human Genetics at the National Institute for Biotechnology in the Negev (NIBN) and Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel
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  • Idan Cohen,

    1. The Morris Kahn Laboratory of Human Genetics at the National Institute for Biotechnology in the Negev (NIBN) and Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel
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  • Orna Staretz-Chacham,

    1. Division of Pediatrics, Soroka Medical Center, Beer-Sheva, Israel
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  • Hagit Flusser,

    1. Division of Pediatrics, Soroka Medical Center, Beer-Sheva, Israel
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  • Daniella Landau,

    1. Division of Pediatrics, Soroka Medical Center, Beer-Sheva, Israel
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  • Ilan Shelef,

    1. Diagnostic Imaging Institute, Soroka Medical Center, Beer-Sheva, Israel
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  • Yshaia Langer,

    1. The Morris Kahn Laboratory of Human Genetics at the National Institute for Biotechnology in the Negev (NIBN) and Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel
    2. The Genetics Institute, Soroka Medical Center, Beer-Sheva, Israel
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  • Ohad S. Birk

    Corresponding author
    1. The Genetics Institute, Soroka Medical Center, Beer-Sheva, Israel
    • The Morris Kahn Laboratory of Human Genetics at the National Institute for Biotechnology in the Negev (NIBN) and Faculty of Health Sciences, Ben Gurion University, Beer-Sheva, Israel
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  • Communicated by Raymond Dalgleish

  • Contract grant sponsors: Israel Science Foundation (ISF grant 1689/12); the Kahn Foundation.

Correspondence to: Ohad S. Birk, Genetics Institute, Soroka University Medical Center, P.O.B. 151, Beer-Sheva 84101, Israel. E-mail: obirk@bgu.ac.il

ABSTRACT

Autosomal recessive osteogenesis imperfecta (OI) was diagnosed in three unrelated Israeli Bedouin consanguineous families. Fractures were evident in all cases in infancy. Genome-wide linkage analysis ruled out association with any of the known OI genes, and identified a single homozygosity locus of approximately 2 Mb on chromosome 9 common to all affected individuals (maximum multipoint lod score 6.5). Whole exome sequencing identified only a single mutation within this locus that was shared by all affected individuals: a homozygous deletion mutation of exon 4 of TMEM38B, leading to an early stop codon and a truncated protein, as well as low TMEM38B mRNA levels. TMEM38B encodes TRIC-B, a ubiquitous component of TRIC, a monovalent cation-specific channel involved in Ca2+ release from intracellular stores that has been shown to act in cell differentiation. Molecular mechanisms through which a TMEM38B mutation might lead to an OI phenotype are yet to be explored.

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