WDR37

WDR37 is a cytoplasmic WD40-repeat protein that forms a stable obligate complex with the sorting proteins PACS1 and PACS2, serving as a critical regulator of ER calcium signaling in lymphocytes and neuronal function. WDR37 homodimerizes and binds PACS1/PACS2 through the PACS1 furin-binding region; complex formation is required for mutual protein stability, and the disease-associated variant p.(Asp220Gly) specifically abolishes PACS1/PACS2 binding (PMID:34642815, PMID:41279321). Loss of WDR37 causes peripheral lymphopenia by blunting ER calcium release following antigen receptor stimulation, and disruption of the PACS1–WDR37 complex suppresses lymphoproliferative disease by forcing loss of lymphocyte quiescence (PMID:33630350). De novo missense variants in WDR37 cause a neurodevelopmental syndrome; disease-associated variants severely impair WDR37 function as demonstrated by failure to rescue seizure-like phenotypes in Drosophila and dominant-negative larval lethality in zebrafish (PMID:31327508, PMID:31327510).

1. 2019 High

   Establishing that WDR37 is essential for neurological function and that human disease variants are loss-of-function resolved the question of whether patient-identified missense variants are pathogenic — Drosophila null mutants phenocopied neurological deficits rescued by wild-type but not variant human WDR37.

   Evidence Drosophila null allele with UAS-cDNA rescue of bang sensitivity, climbing, and grip strength

   PMID:31327508

   Open questions at the time

   • Molecular target or binding partner of WDR37 was unknown
   • Mechanism by which WDR37 supports neuronal function was not identified
   • Whether variants act as loss-of-function or dominant-negative was not resolved in this model
2. 2019 Medium

   Zebrafish modeling revealed that missense variants act through a dominant-negative mechanism distinct from haploinsufficiency, and implicated cholesterol biosynthesis as a downstream pathway — heterozygous missense fish died while frameshift heterozygotes survived.

   Evidence CRISPR-Cas9 zebrafish mutagenesis with RNA-seq transcriptomics

   PMID:31327510

   Open questions at the time

   • Cholesterol pathway upregulation was correlative; direct mechanistic link to WDR37 was not established
   • Cytoplasmic localization was confirmed but specific organelle association was not resolved
   • Whether dominant-negative mechanism involves sequestration of a binding partner was unknown
3. 2021 High

   Identification of PACS1 and PACS2 as direct physical partners of WDR37 answered the central question of what WDR37 binds, and the finding that the disease variant p.(Asp220Gly) specifically disrupts this interaction connected the binding interface to pathogenesis.

   Evidence Co-immunoprecipitation, yeast two-hybrid, and immunocytochemistry in human cells with wild-type and variant WDR37

   PMID:34642815

   Open questions at the time

   • Structural basis of the WDR37–PACS1 interaction was not resolved
   • Functional consequence of the interaction for cell physiology was not tested in this study
   • Whether all disease variants disrupt PACS binding was not determined
4. 2021 High

   Forward genetics in mice established the first physiological function of the PACS1–WDR37 complex: regulation of ER calcium release in lymphocytes, linking the complex to antigen receptor signaling, lymphocyte quiescence, and peripheral lymphocyte homeostasis.

   Evidence Wdr37-knockout mice, calcium flux assays in lymphocytes, and suppression of lymphoproliferative disease models

   PMID:33630350

   Open questions at the time

   • Direct mechanism by which the complex regulates ER calcium stores (e.g., target channel or pump) was not identified
   • Whether the calcium signaling role extends to neurons to explain neurodevelopmental phenotypes was not tested
   • Downstream events linking blunted calcium flux to lymphopenia were not fully dissected
5. 2025 High

   Cryo-EM structure of the PACS1–WDR37 complex revealed the molecular interface (PACS1 furin-binding region binding WDR37) and established mutual protein stabilization, while showing that the PACS1-R203W pathogenic variant does not disrupt complex formation but remains dependent on WDR37 for stability — opening a therapeutic degradation strategy.

   Evidence Cryo-EM structure determination, mutagenesis, targeted proteolytic degradation assay (preprint)

   PMID:41279321

   Open questions at the time

   • Preprint; awaits peer review
   • Lipid-binding activity of the FBR C2-like domain is inferred from structural homology but not biochemically validated
   • Whether WDR37 degradation-based therapeutic approach is effective in vivo remains untested

• The direct molecular mechanism by which the PACS1–WDR37 complex regulates ER calcium release remains unknown — no specific calcium channel, pump, or lipid-signaling intermediate has been identified as a downstream effector.
• No ER calcium channel or SERCA pump interaction has been demonstrated
• Whether the phospholipid-binding capacity of the FBR mediates ER membrane association is untested
• The neuronal function of WDR37 has not been connected to the calcium-signaling mechanism defined in lymphocytes