Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome—Osteogenesis imperfecta phenotypic spectrum

Authors

  • Maria Trinidad Puig-Hervás,

    1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
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    • These authors contributed equally to this work.

  • Samia Temtamy,

    1. Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
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    • These authors contributed equally to this work.

  • Mona Aglan,

    1. Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
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    • These authors contributed equally to this work.

  • Maria Valencia,

    1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
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  • Víctor Martínez-Glez,

    1. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
    2. Instituto de Genética Médica y Molecular, Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
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  • María Juliana Ballesta-Martínez,

    1. Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
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  • Vanesa López-González,

    1. Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
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  • Adel M. Ashour,

    1. Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
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  • Khalda Amr,

    1. Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt
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  • Veronica Pulido,

    1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
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  • Encarna Guillén-Navarro,

    1. Unidad de Genética Médica, Servicio de Pediatría, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
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  • Pablo Lapunzina,

    1. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
    2. Instituto de Genética Médica y Molecular, Hospital Universitario La Paz-IdiPaz, Universidad Autónoma de Madrid, Madrid, Spain
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  • José A. Caparrós-Martín,

    1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
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  • Victor L. Ruiz-Perez

    Corresponding author
    1. Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
    2. Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
    • Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029, Spain.
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  • Communicated by Raymond Dalgleish

Abstract

PLOD2 and FKBP10 are genes mutated in Bruck syndrome (BS), a condition resembling osteogenesis imperfecta (OI), but that is also typically associated with congenital joint contractures. Herein, we sought mutations in six consanguineous BS families and detected changes in either PLOD2 or FKBP10 in all cases. Two probands were found with a homozygous frameshift mutation in the alternative exon 13a of PLOD2, indicating that specific inactivation of the longer protein isoform encoded by this gene is sufficient to cause BS. In addition, by homozygosity mapping, followed by a candidate gene approach, we identified a homozygous donor splice site mutation in PLOD2 in a patient with autosomal-recessive OI (AR-OI). Screening of additional samples also revealed compound heterozygous mutations in PLOD2 in two brothers, one affected with mild AR-OI and the other with mild BS. Thus, PLOD2 in addition to causing BS is also associated with AR-OI phenotypes of variable severity. Hum Mutat 33:1444–1449, 2012. © 2012 Wiley Periodicals, Inc.

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