Whole-Exome Re-Sequencing in a Family Quartet Identifies POP1 Mutations As the Cause of a Novel Skeletal Dysplasia

Evgeny A Glazov,Gethin P Thomas,Emma L Duncan,Tony J Kenna,Matthew A Brown,Marina Donskoi,Andreas Zankl,Graeme R Clark,Marshall Horwitz

doi:10.1371/journal.pgen.1002027

Evgeny A Glazov, Gethin P Thomas + Show 7 more

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https://doi.org/10.1371/journal.pgen.1002027

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Abstract

Recent advances in DNA sequencing have enabled mapping of genes for monogenic traits in families with small pedigrees and even in unrelated cases. We report the identification of disease-causing mutations in a rare, severe, skeletal dysplasia, studying a family of two healthy unrelated parents and two affected children using whole-exome sequencing. The two affected daughters have clinical and radiographic features suggestive of anauxetic dysplasia (OMIM 607095), a rare form of dwarfism caused by mutations of RMRP. However, mutations of RMRP were excluded in this family by direct sequencing. Our studies identified two novel compound heterozygous loss-of-function mutations in POP1, which encodes a core component of the RNase mitochondrial RNA processing (RNase MRP) complex that directly interacts with the RMRP RNA domains that are affected in anauxetic dysplasia. We demonstrate that these mutations impair the integrity and activity of this complex and that they impair cell proliferation, providing likely molecular and cellular mechanisms by which POP1 mutations cause this severe skeletal dysplasia.

Highlights

Skeletal dysplasias are a group of genetic disorders affecting skeletal development that cause deficiencies and deformities of the limbs and spine, dwarfism, or abnormal bone strength
Skeletal dysplasias are usually inherited as monogenic Mendelian traits or occur as a result of de novo mutations
We report identification of mutations in human POP1 gene as the cause of a severe novel skeletal dysplasia

Summary

Introduction

Skeletal dysplasias (SD) are a group of genetic disorders affecting skeletal development that cause deficiencies and deformities of the limbs and spine, dwarfism, or abnormal bone strength. In this study we report the mapping of mutations causing a severe bone dysplasia in a family of unrelated unaffected parents with two affected siblings. The clinical and radiographic features of the affected siblings showed similarities to anauxetic dysplasia, an autosomal recessive spondylo-epi-metaphyseal dysplasia characterized by extremely short stature [8,9]. Both siblings had severe growth retardation of prenatal onset, a bone dysplasia affecting the epiphyses and metaphyses of the long bones in the lower limbs, and abnormalities of the spine including irregularly shaped vertebral bodies and marked cervical spine instability (Figure 1). Following the functional annotation of the remaining novel SNPs, we focused

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Findings

Materials and Methods