PMC9310169_01
Patient pedigrees and radiographic findings. (A) Patient 1 photo and pedigree. (B) Patient 2 photo and pedigree. (C) Representative MRI image of patient 2.
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F1
In family 2, a 3-year-old boy (Figure 1B) with intellectual disability and speech and motor development delay was recruited for genetic analysis. MRI images (Figure 1C) showed delayed myelination and widening of bilateral frontotemporal extracerebral space.
PMC9310169_02
Patient pedigrees and radiographic findings. (A) Patient 1 photo and pedigree. (B) Patient 2 photo and pedigree. (C) Representative MRI image of patient 2.
fgene-13-892940-g001.jpg
PMC9310169_02_fgene-13-892940-g001.jpg
F1
In family 2, a 3-year-old boy (Figure 1B) with intellectual disability and speech and motor development delay was recruited for genetic analysis. MRI images (Figure 1C) showed delayed myelination and widening of bilateral frontotemporal extracerebral space.
ALG13 mutations and expression. (A) Sanger sequencing confirmation of the c.23T > C mutation in case 1 and his mother. (B) Sanger sequencing confirmation of the c.862C > G mutation in case 2 and his mother. (C) Schematic representations of functional domains of ALG13. The p.V8A mutation of family 1 is located in the Glyco_tans_28 domain at N-terminus (amino acid 3-133). The p.L288V mutation of family 2 is mapped in the OUT domain (amino acid 237-348). (D) Residue p.V8 and p.L288 positions are indicated in red in the 3-dimensional structure of the ALG13 protein.
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F2
Trio-WES analysis for family 1 identified a known pathogenic missense variant (c.23T > C; p.V8A) in the ALG13 gene (NM_001099922.3) and further confirmed by Sanger sequencing (Figure 2A) from both the affected boy and his mother. The p.V8 residue is located in the Glyco_tran_28_C domain (amino acids 3-133) at the N-terminal region of the encoded protein (Figures 2C,D), which involves monogalactosyldiacylglycerol synthase and UDP-N-acetylglucosamine transferase (Pfam, SmartMotif). Sanger sequencing further confirmed this variant (Figure 2B). Smart Motif analysis revealed that the mutation p.L288 is mapped to the OTU domain (amino acids 237-348) in the ALG13 protein (Figures 2C,D), which is OTU-like cysteine protease motif.