Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 17p11.2 Genomic coordinates (GRCh38) : 17:19,020,656-19,051,373 (from NCBI)

TEXT

Cloning and Expression

By sequencing cDNAs randomly selected from human cDNA libraries derived from a 6-week-old embryo or tonsils, followed by searching a DNA sequence database, Feng et al. (1996) identified cDNAs showing sequence similarity to GRB2 (108355). One cDNA identified by them encodes a predicted 217-amino acid protein composed of a central SH2 domain flanked by 2 SH3 domains. This GRB2-like arrangement is characteristic of an adaptor protein apparently lacking catalytic activity. Therefore, the authors named the novel protein GRAP for 'GRB2-related adaptor protein.' GRAP shares 59% amino acid identity with GRB2, 53% identity with Drk, and 49% identity with Sem-5. Antibodies against GRAP recognized a 27-kD polypeptide in human cells. Northern blot analysis of human tissues detected a 2.3-kb GRAP transcript primarily in thymus and spleen.

By immunostaining in the mouse cochlea and inner ear, Li et al. (2019) observed expression of Grap in spiral ganglion neuron fibers innervating auditory hair cells, both inner and outer, as well as the utricular hair cells.

Mapping

Gross (2019) mapped the GRAP gene to chromosome 17p11.2 based on an alignment of the GRAP sequence (GenBank BC035856) with the genomic sequence (GRCh38).

Gene Function

Feng et al. (1996) showed that the GRAP SH2 domain interacted with the ligand-activated receptors c-kit (164920) and EPOR (133171) in vitro. GRAP also formed a stable complex via its SH2 domain with the BCR-ABL oncoprotein. Furthermore, GRAP associated, primarily through its N-terminal SH3 domain, with SOS1 (182530). Feng et al. (1996) concluded that a family of GRB2-like proteins exists and that these proteins couple signals from receptor and cytoplasmic tyrosine kinases to the RAS signaling pathway.

Molecular Genetics

From a cohort of 63 consanguineous multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss, Li et al. (2019) identified 2 Turkish families in which 4 affected individuals (DFNB114; 618456) were homozygous for a missense mutation in the GRAP gene (Q104L; 604330.0001).

Animal Model

By immunostaining for drk, the Drosophila homolog of GRAP, in the hearing organ (Johnston organ, JO) of the fly, Li et al. (2019) demonstrated expression of drk in scolopidia, including mechanosensory neurons, scolopale cells, and cap cells. In addition, drk specifically colocalized with synapsin (see 313440) at synapses. Mosaic animals with homozygous deletion of drk in the antenna and eye exhibited severe locomotor deficits, suggestive of strong defects in gravity sensing. Examination of cellular morphology in heterozygous flies revealed disorganized scolopidia, and cell markers labeling JO neurons showed a significantly reduced antennal mechanosensory motor center (AMMC) area, suggesting that drk is required for functional and morphologic integrities of the scolopidia, sensory neurons, and the AMMC brain neuropil. The drk mutant flies exhibited deficits in negative geotaxis behavior, which could be significantly rescued by wildtype, but not mutant, GRAP.

ALLELIC VARIANTS 1 Selected Example):

.0001 DEAFNESS, AUTOSOMAL RECESSIVE 114

GRAP, GLN104LEU
SNP: rs370564476, gnomAD: rs370564476, ClinVar: RCV000782131

In 4 affected individuals from 2 consanguineous Turkish families with nonsyndromic congenital profound sensorineural hearing loss (DFNB114; 618456), Li et al. (2019) identified homozygosity for a c.311A-T transversion (c.311A-T, NM_006613.3) in the GRAP gene, resulting in a gln104-to-leu (Q104L) substitution at a conserved residue within the SH2 domain. The mutation segregated with disease in both families, and was not found in more than 500 Turkish exomes. The variant was present at very low frequency in the gnomAD database (allele frequency, 0.000004129). Shared ancestry of the variant and surrounding region encompassing approximately 1.9 Mb was demonstrated via flanking SNP genotypes.