Syndromic X-linked intellectual disability segregating with a missense variant in RLIM

Abstract

We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A4G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…RLIM variants identified in these families were reported earlier with limited clinical information [3,5]. Family B, included in the clinical assessment and functional assays reported here, has been published before [4]. Families C, D, and F have been revisited and/or were reevaluated clinically.…”

“…Heterozygous RLIM female carriers have highly skewed XCI XCI studies were performed on blood leukocytes or skin fibroblasts of fourteen heterozygous female carriers from five families (B [4], C, F, G, and H) and five noncarrier female relatives. While in thirteen female carriers XCI was (highly) skewed (90-100%), one female carrier showed less skewing (87%, F.IV:8).…”

“…This protein serves as a cofactor promoting or inhibiting transcription factor activity and acts as an E3 ubiquitin ligase ubiquitinating its target proteins for subsequent degradation by the proteasome [1,2]. In humans, rare nucleotide changes in RLIM (MIM 300379) were identified recently in four families with X-linked intellectual disability (XLID) [3,4], with clinical information reported for one family [4] and for a second family published in Spanish [5]. While our current understanding of the functions of human RLIM is sparse, its mouse ortholog (Rlim/Rnf12) has been studied in vitro [6,7] and in vivo [6,8].…”

Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

“…RNF12 mutations cause an X-linked neurodevelopmental disorder termed Tonne-Kalscheuer Syndrome (TOKAS) (Frints et al, 2018;Hu et al, 2016;Tonne et al, 2015), which is underpinned by impaired RNF12 E3 ubiquitin ligase activity resulting in deregulated neuronal differentiation (Bustos et al, 2018). Thus, we hypothesised that SRPK phosphorylates and regulates RNF12, which may represent functional diversification of SRPKs in developmental signalling.…”

“…Mutations in RNF12 cause a neurodevelopmental disorder termed Tonne-Kalscheuer Syndrome (TOKAS), which is a syndromic form of X-linked intellectual disability (Frints et al, 2018;Hu et al, 2016;Tonne et al, 2015). We showed previously that TOKAS mutations specifically impair RNF12…”