MAP3K12

Chr 12

mitogen-activated protein kinase kinase kinase 12

Also known as: DLK, HP09298, MEKK12, MUK, ZPK, ZPKP1

NCBI Gene: 7786 ENSG00000139625 UniProt: Q12852 OMIM: 600447

This serine/threonine protein kinase is predominantly expressed in neurons and regulates transcription through non-canonical MAPK signaling pathways, forming complexes with transcription factors like CREB. Mutations cause autosomal dominant neurodevelopmental disorders with intellectual disability and seizures. The gene is extremely intolerant to loss-of-function variants (pLI ~1.0), indicating that haploinsufficiency likely underlies the pathogenic mechanism.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the serine/threonine protein kinase family. This kinase contains a leucine-zipper domain and is predominately expressed in neuronal cells. The phosphorylation state of this kinase in synaptic terminals was shown to be regulated by membrane depolarization via calcineurin. This kinase forms heterodimers with leucine zipper containing transcription factors, such as cAMP responsive element binding protein (CREB) and MYC, and thus may play a regulatory role in PKA or retinoic acid induced neuronal differentiation. Alternatively spliced transcript variants encoding different proteins have been described.[provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.07

LOEUF· LoF intol.

Multiple*

Mechanism· predicted