Exome sequencing reveals a nonsense mutation in MMP13 as a new cause of autosomal recessive metaphyseal anadysplasia.
Metaphyseal anadysplasia (MANDP) is an uncommon chondrodysplasia characterized by early-onset metaphyseal dysplasia and short stature that improves with age. MANDP is caused by mutations in the matrix metalloproteinase (MMP) 9 and 13 genes. Autosomal dominant (AD) MANDP has been described as more severe, and has been associated with dominant-negative MMP13 mutations that suppress activity of both MMP9 and MMP13; autosomal recessive (AR) MANDP has been described as a milder form associated with AR missense mutations in MMP9 or MMP13. Here we describe the molecular characterization of skeletal dysplasia in two brothers who presented with short stature and mixed epiphyseal and metaphyseal dysplasia. Whole-exome sequencing (WES) identified a homozygous C>T transition mutation in exon 2 of MMP13 (c.325C>T) on chromosome 11q22.2 resulting in a premature stop codon p.(R109*) that is predicted to abolish MMP13 activity. This report extends the MANDP phenotype by illustrating that AR nonsense mutations in MMP13 can lead to short stature that persists beyond childhood.
1] Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA [2] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Dong
D
Li
1] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA [3] Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
David R
DR
Weber
1] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Matthew A
MA
Deardorff
1] Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA [2] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Hakon
H
Hakonarson
1] Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA [2] Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA, USA [3] Center for Bone Health, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Michael A
MA
Levine
D000293:Adolescent; D002648:Child; D018389:Codon, Nonsense; D005091:Exons; D005808:Genes, Recessive; D006801:Humans; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D035781:Siblings
D018389:Codon, Nonsense; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13