Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation Linda S. Weaving, John Christodoulou, Sarah.

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Mutations of CDKL5 Cause a Severe Neurodevelopmental Disorder with Infantile Spasms and Mental Retardation Linda S. Weaving, John Christodoulou, Sarah L. Williamson, Kathie L. Friend, Olivia L.D. McKenzie, Hayley Archer, Julie Evans, Angus Clarke, Gregory J. Pelka, Patrick P.L. Tam, Catherine Watson, Hooshang Lahooti, Carolyn J. Ellaway, Bruce Bennetts, Helen Leonard, Jozef Gécz The American Journal of Human Genetics Volume 75, Issue 6, Pages 1079-1093 (December 2004) DOI: 10.1086/426462 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family 1, showing results of microsatellite-exclusion mapping. Haplotypes were derived using Cyrillic v2 software (Cyrillic Software) and are shown as differently shaded bars. The black bars represent grandpaternal alleles, the gray bars represent grandmaternal alleles, and the striped bars represent paternal alleles. Candidate regions are indicated by boxes. X-inactivation patterns are shown as ratios below the haplotypes. Microsatellites used in this study and their chromosomal band and map positions are given at the far left of the pedigree. Map distances were derived from the Cedar Genetics Map of the X Chromosome, the Ensembl Human Genome Browser, and the Integrated X Chromosome Database. The approximate positions of each of the candidate genes screened in this family are also indicated. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 IVS13-1G→A mutation of CDKL5 in family 2. Chromatograms of the CDKL5 sequence that is mutated in family 2 are shown. A G-to-A transversion involving the intron 13 splice-acceptor site was identified in blood DNA from the subject with an atypical RTT–like phenotype (II:1) but not in her half sister (II:2) with classical RTT or either of her parents. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 c.183delT mutation of CDKL5 in family 1. A chromatogram of the CDKL5 sequence that is mutated in family 1 is shown. Nucleotide numbers begin from the A of the translation start codon in exon 2. Individual ID numbers are derived from figure 1. A deletion of nucleotide 183 was observed in the blood DNA of affected individuals (III:1, III:2, and III:3) but not in unaffected family members. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 cDNA and translated product of the CDKL5 IVS-1G→A mutation. A, Sequence chromatograms of representative cDNA clones isolated from II:1 (family 2) blood RNA/cDNA. In 5 (16.6%) of 30 clones examined, a c.2047delG CDKL5 cDNA was observed. B, Illustration of the creation of a novel intron 13 acceptor splice site as a result of the IVS13-1G→A mutation in CDKL5 of individual II:1 from family 2. The protein sequence is shown below the genomic sequence. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 5 Schematic representation of the CDKL5 gene. CDKL5 exons are indicated by black boxes, and the last four exons of RS1, a gene overlapping CDKL5, are indicated by white boxes. The alternative-splicing patterns are indicated below the diagram for the known isoforms, I and II. Mutations and associated phenotypes that have been reported to date in association with CDKL5 mutations are given above the diagram, and those described in the present study are shown in bold. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 6 Expression of CDKL5 in the mouse brain. A and B, Expression of Stk9 in the brain of wild-type postnatal week-8 mouse (A, antisense riboprobes; B, sense riboprobes). C, Expression of Mecp2 in the brain of wild-type postnatal week-8 mouse. D, Western-blot analysis showing the absence of the 75-kDa Mecp2 protein in the brain of the Mecp2 mutant male mouse, confirming that a null mutation has been generated by deleting the sequence coding the transcription-repression domain and the C-terminal of the protein (G. J. Pelka, C. Watson, T. Radziewic, M. Hayward, and P. P. L. Tam, unpublished data). E and F, Expression of Stk9/Cdkl5 in the brain of postnatal week-8 Mecp2−/Y mutant male mouse (E, antisense riboprobes; F, sense riboprobes). In situ hybridization was performed on parasagittal slices of the mouse brain. Abbreviations for brain regions: bg = basal ganglia; cb = cerebellum; cc = cerebral cortex; cp = caudate-putamen; hf = hippocampal formation; ic = inferior colliculi; ob = olfactory bulb; sc = superior colliculi; th= thalamus. The American Journal of Human Genetics 2004 75, 1079-1093DOI: (10.1086/426462) Copyright © 2004 The American Society of Human Genetics Terms and Conditions