Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy

Grażyna T Truszkowska,Angelika Muchowicz,Tomasz Zieliński,Agnieszka Pollak,Anna Biernacka,Rafał Płoski,Piotr Gasperowicz,Katarzyna Kozar-Kamińska,Zofia T Bilińska,Piotr Stawiński,Joanna Kosińska

doi:10.1038/s41598-017-03189-8

Abstract

The genetic background of dilated cardiomyopathy is highly heterogeneous, with close to 100 known genes and a number of candidates described to date. Nebulin-related-anchoring protein (NRAP) is an actin-binding cytoskeletal protein expressed predominantly in striated and cardiac muscles, and is involved in myofibrillar assembly in the foetal heart and in force transmission in the adult heart. The homozygous NRAP truncating variant (rs201084642), which is predicted to introduce premature stop codon into all NRAP isoforms, was revealed in the dilated cardiomyopathy patient using whole exome sequencing. The same genotype was detected in the asymptomatic proband’s brother. The expression of the NRAP protein was undetectable in the patient’s heart muscle by the Western blot. Genotyping for rs201084642 in the ethnically matched cohort of 231 dilated cardiomyopathy patients did not reveal any additional subjects with this variant. Our findings suggest that the biallelic loss-of-function mutation in NRAP could constitute a relatively rare, low-penetrance genetic risk factor for dilated cardiomyopathy.

Highlights

Nebulin-related anchoring protein (NRAP), expressed in the heart and in striated muscles, is the second largest member of the actin-binding cytoskeletal proteins from nebulin family (193–196 kDa in humans)[1]
Our study is the first description of a dilated cardiomyopathy (DCM) patient with homozygous truncating mutation in the Nebulin-related-anchoring protein (NRAP) gene
The NRAP NM_198060.3:c.4504C > T:p.Arg1502* variant is present in the ExAC database with low frequency (AF-0.0002636); no homozygous LoF variants were reported in the ExAC or in the literature

Summary

Introduction

Nebulin-related anchoring protein (NRAP), expressed in the heart and in striated muscles, is the second largest member of the actin-binding cytoskeletal proteins from nebulin family (193–196 kDa in humans)[1]. In adult mice and humans NRAP expression is limited to: (i) terminal bundles of actin filaments at the myotendinous junctions of skeletal muscles, and (ii) the intercalated discs of the heart muscles and is not observed in mature sarcomeres[1, 4,5,6]. During cardiomyocyte development in the foetal heart, NRAP is involved in myofibrillar assembly[3] and links terminal actin filaments to membrane complexes in the adult heart ( potentially playing a role in force transmission from the sarcomere to the extracellular matrix)[1, 7]. Despite evidence that NRAP plays a role in both in the developing heart and the adult heart, no variants in this gene have been so far conclusively associated with cardiac disease

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