RettBASE: Rett syndrome database update

Abstract

Rett syndrome (RTT) is an X-linked progressive neurodevelopmental disorder that primarily affects females. Mutations in the MECP2 gene have been attributed as the major genetic cause of RTT. Recently, mutations in CDKL5 and FOXG1 genes have also been suggested to give rise to RTT, although subsequent more extensive studies suggest that diseases resulting from mutations in these two genes should be considered as distinct clinical entities. While the genetic basis for the RTT has been recognized, so far there is no effective cure for the disease and the treatments available are mainly aimed at ameliorating clinical problems associated with the disorder. The swift identification of the mutations in children is crucial for pursuing the best therapeutic care. RettBASE was created in 2002 as a MECP2 variant database and has grown to become a comprehensive variant database for RTT and related clinical phenotypes, containing a curated collection of variants for MECP2, CDKL5, and FOXG1 genes. Here, we describe the development and growth of RettBASE after its inception in 2001. Currently, RettBASE holds a total of 4,668 variants in MECP2, 498 variants in CDKL5, and 64 variants in FOXG1.

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

“…Most of the pathogenic mutations are located in the kinase catalytic domain (Fig A; Krishnaraj et al , ), and we investigated the impact of pathogenic kinase domain mutations Gly 20 Asp (Raymond et al , ), Leu 64 Pro (Fichou et al , ), Ile 72 Thr (Saletti et al , ), Arg 178 Trp (Nemos et al , ) and Gln 219 Pro (Hagebeuk et al , ). We also investigated a series of CDKL5 variants that are either benign: Gln 791 Pro (Tao et al , ) and Val 999 Met (Nectoux et al , ) or of uncertain significance: Leu 302 Phe (Liang et al , ), Asn 399 Thr (Sprovieri et al , ), Val 718 Met (Krishnaraj et al , ) and Val 793 Ala (Archer et al , ; Fig A). HEK293 cells were co‐transfected with HA‐tagged MAP1S and CDKL5 (wild type “WT”, K 42 R kinase‐dead “KD” or other mutants).…”

“… Pathogenic and non‐pathogenic CDKL5 variants. Schematic diagram shows modular domains in CDKL5 and the position of amino acid substitutions in humans that are either pathogenic, non‐pathogenic or of unknown consequence according to RettBASE ( http://mecp2.chw.edu.au/cdkl5/cdkl5_variant_list_copy.php; Krishnaraj et al , ). NES: nuclear export signal; NLS: nuclear localization signal. Generation of CDKL5 knockout human cells.…”

Neuronal non-CG methylation is an essential target for MeCP2 function

“…Note: the region of MeCP2 replaced was shorter than the minimal fragment required for binding to methylated DNA (Nan et al, 1993). This region comprises the highly conserved sequence among MBD family members and contains all RTT-causing missense mutations in the MBD cluster, listed on RettBASE: http://mecp2.chw.edu.au/ (Krishnaraj et al, 2017). The region is flanked by proline residues (disrupting protein structure), which were selected as the junctions in MM2 (P93 and P165 of MeCP2).…”

Genome‐wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signaling pathways and cellular functions as potential therapeutic targets

“…Recent estimates recognize that around 95% of classical Rett syndrome cases and 75% of atypical Rett syndrome cases have mutations in MECP2 (Krishnaraj, Ho, & Christodoulou, ). To date, over 900 unique variants have been identified within the MECP2 gene with about 500 being pathogenic or likely pathogenic and the rest being benign, likely benign, or variants of unknown significance (Krishnaraj et al, ).…”