PMC9458848_01
Brain magnetic resonance imaging (MRI) findings of the proband. (A) Dysgenesis of the corpus callosum from sagittal view shown on axial T1-weighted images. (B) Periventricular white matter hyperintense lesions on FLAIR images.
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F1
Brain magnetic resonance imaging showed dysgenesis of the corpus callosum (Figure 1A) and periventricular leukomalacia (Figure 1B).
A two-generation family pedigree and Sequencing results of DDHD2. (A) Heterozygous individuals carrying either mutation are presented with half-filled shaded areas. The arrow indicates the proband. (B) Sequencing results showed that c.168G>C (p.Trp56Cys) was inherited from the mother, whereas c.1505T>C (p.Phe502Ser) was inherited from the father.
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F2
Sanger sequencing confirmed that her mother and sister carried the c.168G>C (p.Trp56Cys) mutation and her father carried the c.1505T>C (p.Phe502Ser) mutation (Figures 2A,B).
Mutation analysis of DDHD2. (A) Amino acid sequence alignment of DDHD2 from different species. Mutant amino acids 56 (tryptophan) and 502 (phenylalanine) are highly conserved across species. (B) Secondary structure diagram of DDHD2 protein. The p.Trp56Cys mutation located in the WWE domain and the p.Phe502Ser mutation located in the DDHD2 domain. (C) Protein molecular models of wild type (WT) and mutant DDHD2 protein (Mutant).
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F3
Comparative amino acid sequence alignment of DDHD2 across different species revealed that the affected amino acids 56 (tryptophan) and 502 (phenylalanine) are highly conserved (Figure 3A). The altered amino residues 56 (tryptophan) and 502 (phenylalanine) in the proband are located in the WWE and DDHD domains, respectively (Figure 3B). Three-dimensional structural modeling of the DDHD2 protein showed that the mutations did not change the hydrogen bonding in protein, but both mutations resulted in changes in side chain size and space ratio compared with the wild type (Figure 3C), which might lead to changes in the conformation of the DDHD2 protein.