HECW2

Chr 2

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2

Also known as: NDHSAL, NEDL2

NCBI Gene: 57520 ENSG00000138411 UniProt: Q9P2P5

The protein functions as an E3 ubiquitin ligase that regulates neural crest cell proliferation, migration and differentiation through GDNF/Ret signaling, and also stabilizes endothelial cell junctions via angiomotin-like 1 regulation. Loss-of-function mutations cause autosomal dominant neurodevelopmental disorder with hypotonia, seizures, and absent language. The protein is extremely intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of a family of E3 ubiquitin ligases which plays an important role in the proliferation, migration and differentiation of neural crest cells as a regulator of glial cell line-derived neurotrophic factor (GDNF)/Ret signaling. This gene also plays an important role in angiogenesis through stabilization of endothelial cell-to-cell junctions as a regulator of angiomotin-like 1 stability. The encoded protein contains an N-terminal calcium/lipid-binding (C2) domain involved in membrane targeting, two-four WW domains responsible for cellular localization and substrate recognition, and a C-terminal homologous with E6-associated protein C-terminus (HECT) catalytic domain. Naturally occurring mutations in this gene are associated with neurodevelopmental delay, hypotonia, and epilepsy. The decreased expression of this gene in the aganglionic colon is associated with Hirschsprung's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeurodevelopmental disorder with hypotonia, seizures, and absent language

Clinical highlights

Gene-disease validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.26

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

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