PMC6783574_01
Pedigree diagrams, mutation detection, and conservation analysis. Pedigree of the family and the arrow indicates the proband (A). Sequencing results showed that the frameshift mutation (c.2491_2497del) was found in the patient and his father, and the missense mutation (c.2923 C > T) was found in the patient and his mother (B). Protein alignment showed conservation of the R831 and R975 residue of RAG1 across 12 species (C).
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He was the second child of healthy nonconsanguineous parents ( Figure 1A ), and born weighing 3.7 kg and had a 5-min Apgar score of 10 at full term. C > T, p.R975W) in exon 2 of RAG1 based on phenotype and genotype ( Figure 1B ). Comparison of RAG1 protein sequences across 12 distantly related animal species indicated that these mutations occurred at an evolutionarily conserved site ( Figure 1C ).
Homology modeling of wild-type and mutant RAG1. Modeled structures of wild-type and mutant RAG1 protein (A, B). Neighboring residues of R975 in the wild-type RAG1 and 975W in the mutated RAG1. H bonds predicted are shown by green dashed line and Arabic numbers (C, D). Structure of p.831_833 in wild-type RAG1 and p.831_833del in the mutated RAG1
(E, F).
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Both mutations can affect the protein structure by forming a truncated protein or by changing the hydrogen bonding distance and the spatial conformation ( Figure 2 ).