关键词: 糖基磷脂酰肌醇生物合成缺陷15型, GPAA1基因, 变异图谱, 遗传咨询

Abstract:

Glycosylphosphatidylinositol biosynthesis deficiency 15 (GPIBD15, MIM: 617810) is an autosomal recessive inherited metabolic disorder caused by mutations in the GPAA1 gene. It is primarily characterized by global developmental delay, intellectual disability, early-onset epileptic seizures, hypotonia, and cerebellar atrophy. In this study, we reported a child diagnosed with GPIBD15 whose main clinical manifestations included dysplasia and cerebral dysfunction. We performed whole-exome sequencing on the patient and his parents. The patient was found to harbor compound heterozygous mutations c.1288C>T（p.P430S） and c.1621C>T（p.R541W） in the GPAA1 gene. The c.1288C>T（p.P430S） variant was inherited from the father, while the c.1621C>T（p.R541W） variant was inherited from the mother. Pathogenicity prediction, evolutionary conservation analysis and protein structure prediction analysis of these mutation sites showed that the variants are deleterious and located at highly conserved residues. These mutations lead to obvious changes in the secondary and tertiary structures of the protein, suggesting that they may affect protein function. To further investigate their functional impact, we constructed plasmid expression vectors harboring the c.1288C>T（p.P430S） and c.1621C>T（p.R541W） mutations and transfected them into HEK293T cells. We observed that co-transfection of the two mutant constructs significantly increased GPAA1 mRNA expression levels, while the corresponding protein expression levels were markedly decreased. Subcellular localization analysis showed no apparent difference between the wild-type and mutant proteins. In conclusion, we report a case of GPIBD15 caused by two novel compound heterozygous mutations in the GPAA1 gene. The pathogenic mechanism may be associated with mutation-induced structural alterations and reduced protein expression. Our findings expand the mutational spectrum of GPAA1 and provide valuable insights for early diagnosis and genetic counseling of patients with GPIBD15.

Key words: glycosylphosphatidylinositol biosynthesis deficiency 15, GPAA1 , gene, mutational spectrum, genetic counseling