A <i>CDKL5</i> mutated child with precocious puberty

Saletti, Veronica; Canafoglia, Laura; Cambiaso, Paola; Russo, Silvia; Marchi, Margherita; Riva, Daria

doi:10.1002/ajmg.a.32806

Cited by 21 publications

(13 citation statements)

References 49 publications

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“…The prevalence of CPP in children with cerebral palsy and moderate or severe motor impairment is unknown, as the available data are limited (15,33,34). A higher prevalence of variable degrees of early sexual maturation was reported in 161 girls with neonatal encephalopathy As expected, our patients also frequently displayed other types of alteration to brain structure (data not shown).…”

Section: Discussionsupporting

confidence: 54%

“…A few groups have reported the epidemiology of non-isolated CPP either at their own institutions (7,8,9,10,11) or over multiple institutions (12,13,14). These studies were limited by the inclusion solely of patients with CNS lesions only, with other associated disorders being evaluated imprecisely, mostly through case reports (15,16,17,18,19).…”

Section: Introductionmentioning

confidence: 99%

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High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

Wannes

Elmaleh‐Bergès

Simon

et al. 2018

European Journal of Endocrinology

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Objective Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes. Design and Methods This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus. Results In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7). Conclusion Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

Wannes

Elmaleh‐Bergès

Simon

et al. 2018

European Journal of Endocrinology

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“…We next investigated the impact of pathogenic mutations on the activity of CDKL5 towards MAP1S. 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).…”

Section: Resultsmentioning

confidence: 99%

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

et al. 2018

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Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho‐Ser900 and CEP131 phospho‐Ser35 confirmed CDKL5‐dependent phosphorylation of these targets in human cells. The phospho‐acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C‐terminal to the phospho‐acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase.

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“…A broad range of pathogenic mutations have been identified (Archer et al 2006;Bahi-Buisson et al 2008bCordova-Fletes et al 2010;Elia et al 2008;Evans et al 2005;Mari et al 2005;Mei et al 2010;Nectoux et al 2006;Nemos et al 2009;Nishimura et al 2008;Pintaudi et al 2008;Psoni et al 2010;Rosas-Vargas et al 2008;Russo et al 2009;Saletti et al 2009;Sartori et al 2009;Scala et al 2005;Tao et al 2004;Weaving et al 2004;White et al 2010). Missense mutations generally occur in the catalytic domain, while small deletions and non-sense or splicing mutations in other regions result in truncated proteins of various lengths (Bertani et al 2006;Nemos et al 2009).…”

Section: Introductionmentioning

confidence: 99%

A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain

et al. 2011

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The X-linked cyclin-dependent kinase-like 5 (CDKL5) gene is an important molecular determinant of early-onset intractable seizures with infantile spasms and Rett syndrome-like phenotype. The gene encodes a kinase that may influence components of molecular pathways associated with MeCP2. In humans there are two previously reported splice variants that differ in the 5' untranslated exons and produce the same 115 kDa protein. Furthermore, very recently, a novel transcript including a novel exon (16b) has been described. By aligning both the human and mouse CDKL5 proteins to the orthologs of other species, we identified a theoretical 107 kDa isoform with an alternative C-terminus that terminates in intron 18. In human brain and all other tissues investigated except the testis, this novel isoform is the major CDKL5 transcript. The detailed characterisation of this novel isoform of CDKL5 reveals functional and subcellular localisation attributes that overlap greatly, but not completely, with that of the previously studied human CDKL5 protein. Considering its predominant expression in the human and mouse brain, we believe that this novel isoform is likely to be of primary pathogenic importance in human diseases associated with CDKL5 deficiency, and suggest that screening of the related intronic sequence should be included in the molecular genetic analyses of patients with a suggestive clinical phenotype.

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A CDKL5 mutated child with precocious puberty

Cited by 21 publications

References 49 publications

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

A novel transcript of cyclin-dependent kinase-like 5 (CDKL5) has an alternative C-terminus and is the predominant transcript in brain

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