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

Authors:
Open Access
Publisher website
Google Scholar
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. 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. Molecular analyses presented in our work provide an important link between the pathogenesis of the disease and basic cellular processes including RNA processing and the cell cycle. We posit that our work will also have an immediate impact on assessment and counselling of novel cases of severe short stature.

This publication has 21 references indexed in Scilit: