GPSM2 belongs to a group of proteins that modulate the activation of G proteins that transduce extracellular signals received by cell surface receptors into integrated cellular responses. GPSM2 plays an essential role in maintaining cell polarity and spindle pole orientation. Dysfunction of GPSM2 is found to be associated with the phenotype of multiple micronuclei due to chromosomal mis-segregation and defect in cell division through mis-localization of mitotic spindle regulator protein NuMA.
The GPSM2 gene is located on the short arm of chromosome 1 at 1p13.1 and spans 44.7 kb of genomic DNA with a coding sequence consisting of 14 exons. The GPSM2 protein is made up of 677 amino acids and weights around 76 kDa. It is comprised of seven N-terminal tetratricopeptide (TPR) motifs, a linker domain, and four C-terminal Galphai/0-Loco (GoLoco) motifs that function in guanine nucleotide exchange.
Shahin et al. (2010) carried out a molecular study to identify the genes responsible for inherited hearing loss, by using high-density SNP arrays to genotype the DNA of 155 relatives (including: 78 patients, 28 of their hearing siblings, and 49 parents) from 20 Palestinian consanguineous families with prelingual bilateral autosomal recessive non-syndromic hearing loss (NSHL). In seven affected members in one of the 20 families, Shahin et al. (2010) found linkage to a 3.1-Mb region on chromosome 1p13.3 (lod score of 5.16) between markers rs17542571 and rs1936942, which they designated DFNB82. Since the DFNB82 region overlaps the DFNB32 locus by 833 kb, Shahin et al. (2010) sequenced the two candidate genes in the region of overlap (VAV3, SLC25A24), but they did not find novel variants segregating with NSHL. Later, Walsh et al. (2010) identified, in the affected members of this family, a homozygous c.875C>T transition in the GPSM2 gene, resulting in an arg127-to-ter (p.R127X) substitution that truncates the protein between the second and third TPR motifs. Analysis of lymphoblast RNA showed that the nonsense allele produces a stable mutant transcript. All unaffected parents were found to be heterozygous for the mutation. Walsh et al. (2010) postulated that the R127X mutation causes a defect in the maintenance of cell polarity and spindle orientation in hair and supporting cells of the developing inner ear, indicating that GPSM2 is essential to the development of normal hearing.
Hamzeh et al (2016) studied two brothers affected with Chudley McCullough Syndrome. The patients were born to healthy consanguineous parents and were diagnosed with severe profound bilateral sensorineural hearing loss. Brain CT showed the presence of arachnoid cysts and partial agenesis of the corpus callosum. Sequencing of the entire coding region and exon/intron boundaries of the GPSM2 gene revealed the presence of a novel homozygous mutation in both patients. This c.1055C>A mutation was predicted to result in a truncating p.Ser352* protein change. Since this mutation lies within the linker domain, the truncation was predicted to result in a protein that lacked all its four C-terminal GoLoco motifs. Mice with similar C-terminal mutations were shown to have disruptions in the mitotic orientations in the apical divisions of the dorsolateral brain. Both parents were found to be heterozygous carries for the mutation. This mutation was not found in a database containing 2.5 million variants mostly from the Arabian Peninsula.
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