CRHR1

Chr 17

corticotropin releasing hormone receptor 1

Also known as: CRF-R, CRF-R-1, CRF-R1, CRF1, CRFR-1, CRFR1, CRH-R-1, CRH-R1

NCBI Gene: 1394 ENSG00000120088 UniProt: P34998

This gene encodes a G-protein coupled receptor that binds corticotropin-releasing hormone and urocortin to activate adenylyl cyclase and regulate the hypothalamic-pituitary-adrenal axis stress response. Mutations cause isolated ACTH deficiency, an autosomal recessive disorder presenting in infancy with severe hypoglycemia, failure to thrive, and life-threatening adrenal insufficiency due to impaired cortisol production. The gene is not highly constrained against loss-of-function variants, consistent with the recessive inheritance pattern observed clinically.

ResearchSummary from RefSeq, UniProt

This gene encodes a G-protein coupled receptor that binds neuropeptides of the corticotropin releasing hormone family that are major regulators of the hypothalamic-pituitary-adrenal pathway. The encoded protein is essential for the activation of signal transduction pathways that regulate diverse physiological processes including stress, reproduction, immune response and obesity. Alternative splicing results in multiple transcript variants. Naturally-occurring readthrough transcription between this gene and upstream GeneID:147081 results in transcripts that encode isoforms that share similarity with the products of this gene. [provided by RefSeq, Aug 2016]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.71

Clinical Summary— CRHR1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.71

OE 0.44 (0.28–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.73Z-score

OE missense 0.71 (0.63–0.80)

196 obs / 277.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.44 (0.28–0.71)

0≤0.351.4

Missense OE?0.71 (0.63–0.80)

0≤0.61.4

Synonymous OE?0.91

0≤1.21.6

LoF obs/exp: 12 / 27.2Missense obs/exp: 196 / 277.0Syn Z: 0.76

This gene — mechanism propensity

0.85top 5%

GOF

0.83top 10%

LOF

0.2092th %ile

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

DNprediction above median

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.