Abstract
Background: Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual disability, in which specific associated facial, hand, and skeletal abnormalities are diagnostic features. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. We performed functional studies on this variant and another one, already reported in the literature, involving the same amino acid residue but, to date, without an efficient characterization. Results: Our study demonstrated that the two variants involving residue 189 significantly impaired its kinase activity. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a three-generation family with an X-linked ID.
Highlights
Coffin–Lowry syndrome (CLS) (MIM 303600) is a rare X-linked dominant disorder, first described by Grange S
We reported a novel mutation in the ribosomal S6 kinase 2 (RSK2) gene present in two related patients with different phenotypes characterized by intellectual disability (ID) and peculiar facial dysmorphisms
Western blot analysis revealed standard expression and size of RSK2-I189T and RSK2-I189K proteins compared to wild type protein (Figure 3A)
Summary
Coffin–Lowry syndrome (CLS) (MIM 303600) is a rare X-linked dominant disorder, first described by Grange S. Coffin in 1966 and characterized by intellectual disability (ID) and peculiar facial dysmorphisms, hands, and skeletal malformations [1]. In male patients with CLS, moderate-to-severe intellectual disability, abnormal gait, skeletal abnormalities and characteristic facial changes are the rule. They typically have hypotonia, delayed closure of the anterior fontanel, facial dysmorphisms, short stature, tapering, hyperextensible fingers, and progressive skeletal deformities, whereas carrier females may show a typical CLS phenotype but are commonly mildly affected [1,5]. Methods: In the present study, an unreported missense genetic variant of the ribosomal S6 kinase 2 (RSK2) gene has been identified, by next-generation sequencing, in two related males with two different phenotypes of intellectual disability (ID) and peculiar facial dysmorphisms. Conclusions: We detected a loss-of-function RSK2 mutation with loss in kinase activity in a threegeneration family with an X-linked ID.
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