Till date, 11 hemizygous variants in SMS gene causing Snyder-Robinson syndrome so far reported [6, 14, 15]. All of these were missense mutations and a case of complete LoF variant in SMS is reported in 2020 [16]. Here, we identify the first Pakistani family with a novel pathogenic variant in the SMS gene, which expands the phenotypes and focuses on the characteristics of SRS. The pathogenic variant was absent in the general population (gnom AD https://gnomad.broadinstitute.org/). In this family, patients presented all the clinical features previously described in SRS [6], such as ID, facial dysmorphic features, including long oval midface hypoplasia and bone deformities (Fig. 4). There is wide phenotypic variability in the reported SRS patients, however, as yet, no genotype-phenotype correlation has been described. The SMS gene codes for an enzyme called spermine synthase whose function is the production of spermine from spermidine for polyamine metabolism.
The reported pathogenic variant p.S302L is the substitution of amino acid residue serine by a residue leucine. The pathogenic variant site S302 is buried in the protein interior. As it is shown in Fig. 3D and Fig. 3F, the structure around the S302 pathogenic variant site is present in a very packed and conserved area, and there is no space to adjust the amino acid leucine. The mutated residue is located in a domain that is important for the activity of the protein and in contact with another domain that is also important for the activity. The interaction between these domains could be disturbed by the mutation, which might affect the function of the protein. This pathogenic variant reduced level of spermine synthase in the body with increased spermidine/spermine ratio.
The overall study revealed the molecular mechanism of the causative mutation in SMS gene. As most of theSUMOylation sites follow a canonical consensus motif of ψ -K-X-E/D (ψ, a hydrophobic amino acid, such as A, I, L, M, P, F, V or W; X, any amino acid residue) and this protein has the motif (ψ -K- X-E/D), it may be the target of SUMOylation. The amino acid position 302 is located very close to this motif (297-LILDLS/LMKVLKQD-309, where the S of S/L is WT type, L is the mutant and the bold is the SUMOylated candidate motif) [17, 18], suggesting that the mutation may lead to an alteration of the putative SUMOylation process. Moreover, the pathogenic variant site is highly conserved among the species (Fig. 3F). Therefore, it can be said that this pathogenic variant can significantly affect spermine stability. The described pathogenic variant affects the structural integrity of the protein and halts the protein folding, which could lead to its degradation. The degradation of Spermin Sintase protein causes the X-linked recessive Snyder-Robinson Syndrome.
Conclusion:
In conclusion, only few pathogenic variants have been reported to Snyder-Robinson syndrome. We identify the first Pakistani family carrying a novel variant in the SMS gene, contributing to broad the phenotype associated to this rare syndrome.