Truncation of the CNS-expressed JNK3 in a patient with a severe developmental epileptic encephalopathy

Abstract

We have investigated the breakpoints in a male child with pharmacoresistant epileptic encephalopathy and a de novo balanced translocation t(Y;4)(q11.2;q21). By fluorescence in situ hybridisation, we have identified genomic clones from both chromosome 4 and chromosome Y that span the breakpoints. Precise mapping of the chromosome 4 breakpoint indicated that the c-Jun N-terminal kinase 3 (JNK3) gene is disrupted in the patient. This gene is predominantly expressed in the central nervous system, and it plays an established role in both neuronal differentiation and apoptosis. Expression studies in the patient lymphoblastoid cell line show that the truncated JNK3 protein is expressed, i.e. the disrupted transcript is not immediately subject to nonsense-mediated mRNA decay, as is often the case for truncated mRNAs or those harbouring premature termination codons. Over-expression studies with the mutant protein in various cell lines, including neural cells, indicate that both its solubility and cellular localisation differ from that of the wild-type JNK3. It is plausible, therefore, that the presence of the truncated JNK3 disrupts normal JNK3 signal transduction in neuronal cells. JNK3 is one of the downstream effectors of the GTPase-regulated MAP kinase cascade, several members of which have been implicated in cognitive function. In addition, two known JNK3-interacting proteins, barrestin 2 and JIP3, play established roles in neurite outgrowth and neurological development. These interactions are likely affected by a truncated JNK3 protein, and thereby provide an explanation for the link between alterations in MAP kinase signal transduction and brain disorders.

Characterisation of de novo MAPK10/JNK3 truncation mutations associated with cognitive disorders in two unrelated patients

“…For example, the IL1RAPL1 gene has been implicated in monogenic forms of intellectual disability and autism in several unrelated patients, and recent characterisation of the IL1RAPL1 knockout mouse illuminated disease-associated alterations in the JNK signalling cascade (Pavlowsky et al 2010a, b). These studies, paralleled by our identification of a de novo MAPK10/JNK3 (OMIM 602897) truncation mutation in a patient with a severe neurodevelopmental disorder (Shoichet et al 2006), and the fact that this gene is among those affected by a rearrangement in another patient with a complex physical and cognitive disorder (Baptista et al 2008), make clear that JNKs-in particular the CNS-expressed MAPK10/ JNK3-are candidates for mutation identification in patients with early-onset neurological disorders. Here, we describe the clinical and genetic characterisation of an unrelated patient with a cognitive phenotype harbouring a de novo chromosome rearrangement affecting the MAPK10/JNK3 gene.…”

“…On the derivative chromosome 4, the breakpoint interrupts the MAPK10/JNK3 gene between exons 9 and 10, and the predicted truncated JNK3, presumably expressed predominantly in neural tissue, harbours 267 of 464 amino acids (Shoichet et al 2006). Here, we describe a second patient carrying a similar chromosome rearrangement involving the same region of chromosome 4 and presenting with intellectual disability (ID).…”

“…Importantly, in light of the specific CNS expression of most JNK3 isoforms (Martin et al 1996), we could not validate the presence of truncated protein in patient material; however, we cannot exclude dominant-interfering effects of the mutant protein in nervous tissue where JNK3 isoforms are normally expressed at high levels. Our previous studies on the mutant protein associated with Patient 1 (Shoichet et al 2006) suggest that the truncated JNK3 may actively contribute to defective CNS function via toxic effects. Here we demonstrate that truncated JNK3 proteins are also capable of weak interactions with a set of JNK-associated scaffold proteins, suggesting another potential mode of dominant interference in cells that are haploinsufficient for JNK3.…”

“…We previously reported on a patient with severe cognitive and developmental delay carrying a balanced translocation affecting the c-Jun N-terminal kinase JNK3 (Shoichet et al 2006). On the derivative chromosome 4, the breakpoint interrupts the MAPK10/JNK3 gene between exons 9 and 10, and the predicted truncated JNK3, presumably expressed predominantly in neural tissue, harbours 267 of 464 amino acids (Shoichet et al 2006).…”

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

“…Another chromosome abnormality identified in a patient with a severe developmental delay and CEE consistent with LGS was a balanced translocation t(Y;4)(q11.2;q21), which truncates the c-Jun N-terminal kinase 3 (JNK3) gene 42 .…”