HGNC Approved Gene Symbol: NRAP
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:113,588,714-113,664,041 (from NCBI)
Nebulin (161650) is a giant myofibrillar protein found within the sarcomeres of skeletal muscle. Over 95% of the nebulin protein consists of 185 copies of a 35- to 40-amino acid module. Most of the modules are arranged into a higher order repeating sequence termed a 'nebulin super repeat.' By screening a mouse skeletal muscle library with a human nebulin cDNA, Luo et al. (1997) isolated cDNAs encoding a protein that they called 'nebulin-related anchoring protein,' or NRAP. Sequence analysis predicted that NRAP is a 1,175-amino acid protein with a pI of 9.26. The C-terminal half of NRAP includes an actin-binding domain with homology to the nebulin super repeats. The N-terminal region contains a LIM domain, thought to mediate protein-protein interactions. Northern blot analysis of various mouse tissues revealed that NRAP is expressed as a 6-kb mRNA only in skeletal muscle and heart. Antibodies against NRAP recognized a 185-kD band on Western blots of skeletal and cardiac muscle proteins. Using immunofluorescence, Luo et al. (1997) found that NRAP is localized at the myotendinous junction in skeletal muscle and the intercalated disc in cardiac muscle. The authors suggested that NRAP performs an anchoring function, linking the terminal actin filaments of myofibrils to protein complexes located beneath the sarcolemma. By searching the GenBank database, Luo et al. (1997) identified ESTs encoding the human NRAP homolog.
Luo et al. (1997) mapped the human NRAP gene to 10q24-q26 using PCR of a radiation hybrid panel. By analysis of an interspecific backcross, they found that the mouse NRAP gene is located on chromosome 19 in a region showing homology of synteny with the human 10q23-q26 region.
Associations Pending Confirmation
In a 26-year-old man who developed rapidly progressive symptoms of biventricular heart failure (see CMD1A, 115200) after a prolonged viral-like illness, Truszkowska et al. (2017) performed exome sequencing and identified homozygosity for a c.4504C-T transition in the NRAP gene, resulting in an arg1502-to-ter (R1502X; rs201084642) substitution. His unaffected 36-year-old brother was also homozygous for the variant, for which their unaffected parents were heterozygous. The rs201084642 variant was present in the ExAC database at a frequency of 0.0002636 (32/121,382 alleles) and in an in-house database at a frequency of 0.0037736 (4/1,060). SNP genotyping in a cohort of 231 unrelated Polish patients with dilated cardiomyopathy (CMD) did not reveal any additional homozygotes or heterozygotes for the variant. Cardiac MRI in the proband showed global diffuse hypokinesis of both ventricles, with ejection fractions of 19%, and significantly increased left ventricular volume. He continued to deteriorate and underwent cardiac transplantation 4 months after onset of symptoms. While awaiting transplantation, he experienced 1 episode of sustained ventricular tachycardia treated with cardioversion and implantation of an ICD-VR for secondary prevention. NRAP protein in tissue from the proband's right and left ventricular walls and interventricular septum was undetectable by Western blot. The authors concluded that the biallelic NRAP mutation might have contributed to the proband's cardiac dysfunction, perhaps in conjunction with viral illness and/or other genetic or nongenetic factors, and that biallelic loss-of-function mutations in NRAP could constitute a low-penetrance genetic risk factor for CMD.
Luo, G., Leroy, E., Kozak, C. A., Polymeropoulos, M. H., Horowits, R. Mapping of the gene (NRAP) encoding N-RAP in the mouse and human genomes. Genomics 45: 229-232, 1997. [PubMed: 9339382] [Full Text: https://doi.org/10.1006/geno.1997.4917]
Luo, G., Zhang, J. Q., Nguyen, T.-P., Herrera, A. H., Paterson, B., Horowits, R. Complete cDNA sequence and tissue localization of N-RAP, a novel nebulin-related protein of striated muscle. Cell Motil. Cytoskeleton 38: 75-90, 1997. [PubMed: 9295142] [Full Text: https://doi.org/10.1002/(SICI)1097-0169(1997)38:1<75::AID-CM7>3.0.CO;2-G]
Truszkowska, G. T., Bilinska, Z. T., Muchowicz, A., Pollak, A., Biernacka, A., Kozar-Kaminska, K., Stawinski, P., Gasperowicz, P., Kosinska, J., Zielinski, T., Ploski, R. Homozygous truncating mutation in NRAP gene identified by whole exome sequencing in a patient with dilated cardiomyopathy. Sci. Rep. 7: 3362, 2017. Note: Electronic Article. [PubMed: 28611399] [Full Text: https://doi.org/10.1038/s41598-017-03189-8]