Open AccessMutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay
Author(s) -
Asiri Abdulaziz,
Aloyouni Essra,
Umair Muhammad,
Alyafee Yusra,
Al Tuwaijri Abeer,
Alhamoudi Kheloud M.,
Almuzzaini Bader,
Al Baz Abeer,
Alwadaani Deemah,
Nashabat Marwan,
Alfadhel Majid
Publication year - 2020
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51059
Subject(s) - sanger sequencing , exon , proband , genetics , hypotonia , gene , nonsense mediated decay , rna splicing , rhoa , guanine nucleotide exchange factor , biology , gene mutation , medicine , microbiology and biotechnology , mutation , gene expression , rna , gtpase , signal transduction
Background RAP1GDS1 (RAP1, GTP‐GDP dissociation stimulator 1), also known as SmgGDS, is a guanine nucleotide exchange factor (GEF) that regulates small GTPases, including, RHOA, RAC1, and KRAS. RAP1GDS1 was shown to be highly expressed in different tissue types including the brain. However, mutations in the RAP1GDS1 gene associated with human diseases have not previously been reported. Methods We report on four affected individuals, presenting intellectual disability, global developmental delay (GDD), and hypotonia. The probands’ DNA was subjected to whole‐genome sequencing, revealing a homozygous splice acceptor site mutation in the RAP1GDS1 gene (1444‐1G > A). Sanger sequencing was performed to confirm the segregation of the variant in two Saudi families. The possible aberrant splicing in the patients’ RNA was investigated using RT‐PCR and changes in mRNA expression of the patients were confirmed using qRT‐PCR. Results The identified splice variant was found to segregate within the two families. RT‐PCR showed that the mutation affected RAP1GDS1 gene splicing, resulting in the production of aberrant transcripts in the affected individuals. Quantitative gene expression analysis demonstrated that the RAP1GDS1 mRNA expression in all the probands was significantly decreased compared to that of the control, and Sanger sequencing of the probands’ cDNA revealed skipping of exon 13, further strengthening the pathogenicity of this variant. Conclusion We are the first to report the mutation of the RAP1GDS1 gene as a potential cause of GDD and hypotonia. However, further investigations into the molecular mechanisms involved are required to confirm the role of RAP1GDS1 gene in causing GDD and hypotonia.