CDK19 is disrupted in a female patient with bilateral congenital retinal folds, microcephaly and mild mental retardation

Abstract

Microcephaly, mental retardation and congenital retinal folds along with other systemic features have previously been reported as a separate clinical entity. The sporadic nature of the syndrome and lack of clear inheritance patterns pointed to a genetic heterogeneity. Here, we report a genetic analysis of a female patient with microcephaly, congenital bilateral falciform retinal folds, nystagmus, and mental retardation. Karyotyping revealed a de novo pericentric inversion in chromosome 6 with breakpoints in 6p12.1 and 6q21. Fluorescence in situ hybridization analysis narrowed down the region around the breakpoints, and the breakpoint at 6q21 was found to disrupt the CDK19 gene. CDK19 was found to be expressed in a diverse range of tissues including fetal eye and fetal brain. Quantitative PCR of the CDK19 transcript from Epstein–Barr virus-transformed lymphoblastoid cell lines of the patient revealed ~50% reduction in the transcript (p = 0.02), suggesting haploinsufficiency of the gene. cdk8, the closest orthologue of human CDK19 in Drosophila has been shown to play a major role in eye development. Conditional knock-down of Drosophila cdk8 in multiple dendrite (md) neurons resulted in 35% reduced dendritic branching and altered morphology of the dendritic arbour, which appeared to be due in part to a loss of small higher order branches. In addition, Cdk8 mutant md neurons showed diminished dendritic fields revealing an important role of the CDK19 orthologue in the developing nervous system of Drosophila. This is the first time the CDK19 gene, a component of the mediator co-activator complex, has been linked to a human disease.

Redefining the MED13L syndrome

“…MED13L is only one component of the mediator complex linked to human disease: (i) MED12 gene variants cause Lujan-Fryns syndrome (MIM #309520), 25 Ohdo syndrome (MIM #300895), 26 Opitz-Kaveggia syndrome (MIM #305450), 27 and profound ID that in contrast to the aforementioned syndromes resulted in affected female carriers and truncation of the MED12 protein, 28 (ii) a recurrent homozygous MED17 missense variant has been linked to postnatal progressive microcephaly with seizures and brain atrophy (MIM #613668), 29 (iii) a homozygous MED23 variant causes autosomal recessive nonsyndromic ID (MIM #614249), 30 (iv) a homozygous MED25 variant causes autosomal recessive adult onset axonal Charcot-Marie-Tooth neuropathy (CMT2B2, MIM #605589) 31 and (v) a truncation of CDK19 caused by a chromosome inversion is associated with bilateral congenital retinal folds, microcephaly, and mild ID (MIM #614720). 32 We observe that the MED13L phenotype displays similarities to OpitzKaveggia syndrome, along with key differences (see Table 3). Indeed, MED12 and MED13/MED13L are closely associated with the CDK8 module, which has a distinct role in regulating mediator function and transcription.…”

Cyclin-dependent kinase 8 mediates chemotherapy-induced tumor-promoting paracrine activities

“…CDK8 is required for embryonic development at the preimplantation stage (42), probably because of its role in the pluripotency of embryonic stem cells (24), and CDK19 haploinsufficiency has been linked to a congenital neurological defect (43). CDK8 knockdown did not, however, affect normal cell growth (28,42).…”

Dysregulation of CDK8 and Cyclin C in tumorigenesis

“…CDK19 (also known as CDC2L6, CDK8-like or CDK8L) is the paralog of CDK8 with a highly conserved amino acid sequence in the kinase and cyclin binding domains at the Nterminal regions. Disruption of CDK19 has been linked to microcephaly and mild mental retardation in human (Mukhopadhyay et al, 2010). Both CDK8 and CDK19 contain an identical SMSACRE motif (Sato et al, 2004).…”