Biallelic variants in MESD, which encodes a WNT-signaling-related protein, in four new families with recessively inherited osteogenesis imperfecta
Thao T. Tran,
Rachel B. Keller,
Brecht Guillemyn,
Melanie Pepin,
Jane E. Corteville,
Samir Khatib,
Mohammad-Sadegh Fallah,
Sirous Zeinali,
Fransiska Malfait,
Sofie Symoens,
Paul Coucke,
Peter Witters,
Elena Levtchenko,
Hamideh Bagherian,
Deborah A. Nickerson,
Michael J. Bamshad,
Jessica X. Chong,
Peter H. Byers
Affiliations
Thao T. Tran
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA
Rachel B. Keller
Department of Pathology, University of Washington, Seattle, WA 98195, USA
Brecht Guillemyn
Center for Medical Genetics Ghent, Ghent University Hospital, Department of Biomolecular Medicine, Ghent, Belgium
Melanie Pepin
Department of Pathology, University of Washington, Seattle, WA 98195, USA
Jane E. Corteville
Department of Reproductive Biology, Case Western Reserve University, Cleveland, OH 44106, USA
Samir Khatib
GMDC Al Quds University, P.O. Box 5100, Abu Dis, Palestine
Mohammad-Sadegh Fallah
Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran, Iran
Sirous Zeinali
Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran, Iran; Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
Fransiska Malfait
Center for Medical Genetics Ghent, Ghent University Hospital, Department of Biomolecular Medicine, Ghent, Belgium
Sofie Symoens
Center for Medical Genetics Ghent, Ghent University Hospital, Department of Biomolecular Medicine, Ghent, Belgium
Paul Coucke
Center for Medical Genetics Ghent, Ghent University Hospital, Department of Biomolecular Medicine, Ghent, Belgium
Peter Witters
Center for Metabolic Diseases, University Hospital Leuven, Department of Paediatric Gastroenterology, Hepatology, and Nutrition, Leuven, Belgium
Elena Levtchenko
University Hospital Leuven, Departments of Pediatric Nephrology and Development and Regeneration, Leuven, Belgium
Hamideh Bagherian
GMDC Al Quds University, P.O. Box 5100, Abu Dis, Palestine; Department of Medical Genetics, Kawsar Human Genetics Research Center, Tehran, Iran
Deborah A. Nickerson
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
Michael J. Bamshad
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Jessica X. Chong
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Peter H. Byers
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA; Department of Medicine (Medical Genetics), University of Washington, Seattle, WA 98195, USA; Corresponding author
Summary: The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)—which are associated with a severe form of OI—and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.
