JPH3

Chr 16AD

junctophilin 3

Also known as: CAGL237, HDL2, JP-3, JP3, TNRC22

NCBI Gene: 57338 ENSG00000154118 UniProt: Q8WXH2 OMIM: 605268

The protein forms junctional membrane complexes that link the plasma membrane with the endoplasmic reticulum in brain neurons, providing structural foundation for cross-talk between cell surface and intracellular calcium release channels. CAG/CTG repeat expansions (40-59 repeats) in the 3' UTR cause Huntington disease-like 2 through a loss-of-function mechanism, inherited in an autosomal dominant pattern. The protein is brain-specific and functions in neurons involved in motor coordination and memory.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. CAG/CTG repeat expansion from normally 6-28 repeats to 40-59 repeats in the 3' UTR of this gene have been associated with Huntington disease-like 2 (HDL2). This gene is a member of the junctophilin gene family. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.201 OMIM phenotype

Clinical Summary— JPH3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 0.999

Z-score 4.29

OE 0.04 (0.01–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

-0.32Z-score

OE missense 1.04 (0.97–1.12)

511 obs / 491.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.20)

0≤0.351.4

Missense OE?1.04 (0.97–1.12)

0≤0.61.4

Synonymous OE?1.43

0≤1.21.6

LoF obs/exp: 1 / 23.4Missense obs/exp: 511 / 491.1Syn Z: -5.09

This gene — mechanism propensity

0.4289th %ile

GOF

0.5072th %ile

LOF

0.76top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.20

GOF1 literature citation

Literature Evidence

GOFOur results suggest that the pathogenic mechanism of HDL2 is multifactorial, involving both a toxic gain of function of JPH3 RNA and a toxic loss of JPH3 expression.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References