The RFT1 gene encodes an enzyme involved in N-linked glycosylation. This is a highly conserved process which involves the synthesis and processing of (N)-linked glycans or oligosaccharides on glycoproteins. It begins with the synthesis of a Man(5)GlcNAc(2)-dolichylpyrophosphate intermediate on the cytoplasmic side of the endoplasmic reticulum (ER) membrane. This intermediate is then translocated to the luminal side of the ER membrane. The RFT1 enzyme is responsible for catalyzing this translocation of Man(5)GlcNAc(2)-dolichylpyrophosphate.
Mutations in the RFT1 gene hence lead to enzymatic defects in N-linked glycosylation and are associated with Congenital Disorder of Glycosylation, Type In (CDG1N). This metabolic disorder results in severe developmental delay, mental retardation, seizures, myoclonus, hypotonia, microcephaly and failure to thrive.
The RFT1 gene is located on the short arm of chromosome 3. It spans a length of 59.3 kb of DNA and its coding sequence is contained within 18 exons. The protein product encoded by this gene has a molecular mass of 60.3 kDa and consists of 541 amino acids. The gene is found to be overexpressed in the heart, lymph nodes and monocyte cells. Homozygous and compound heterozygous mutations in the RFT1 gene are associated with CDG1N. These are mainly missense variants that result in a non-functioning RFT1 protein.
Monies et al. (2017) examined the findings of 1000 diagnostic panels and exomes carried out at a next generation sequencing lab in Saudi Arabia. One patient, a 3-year-old male from a consanguineous family, presented with congenital microcephaly, global developmental delay, epilepsy and hematemesis. Using whole exome sequencing, a homozygous mutation (c.775+1G>C) was identified in exon 7 of the patient’s RFT1 gene, associated with CDG1N. Given the atypical presentation of the patient, this case helped in the phenotypic expansion of the disorder.
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