Membrane Contact Sites: Organelle Communication in Disease

Organelles exchange lipids, calcium and signals at membrane contact sites, where tethering proteins hold two membranes close without fusing them. Every organelle makes such contacts, often with several partners at once. Before this project, about twenty disorder entries described a contact-site defect in their own words, with nothing linking them. The membrane_contact_site_dysfunction module now gives them a shared chain:

Loss of organelle tethering at a contact site (trigger)
Disrupted non-vesicular lipid transfer between organelles (key conformance target), with a parallel arm for impaired ER-to-mitochondria calcium transfer
Organelle membrane lipid imbalance, with plasmalogen (ether phospholipid) synthesis at ER-peroxisome contacts as the worked example
Altered organelle morphology, number and distribution
Impaired synapse formation and maturation
Neural cell dysfunction, and (from mouse and ESC-derived models) impaired cardiomyocyte differentiation and maturation

Conformance status

Entry	Organelle pair	Tether / protein	Conforms at
Adult-Onset Proximal Spinal Muscular Atrophy Autosomal Dominant	ER to many	VAPB	trigger; calcium transfer
McLeod Neuroacanthocytosis Syndrome	ER-plasma membrane	XK with VPS13A	lipid transfer
Chorea-acanthocytosis	ER-mitochondria, ER-lipid droplet	VPS13A	lipid transfer
Wolfram Syndrome	ER-mitochondria	wolframin, CISD2	calcium transfer
WFS1-Related Disorder	ER-mitochondria	wolframin	calcium transfer
Intellectual Developmental Disorder With Autism And Dysmorphic Facies	ER-mitochondria, ER-lysosome	PDZD8	calcium transfer
Autosomal Recessive Spinocerebellar Ataxia 20	ER-lipid droplet	SNX14	organelle morphology
Intellectual Disability Autosomal Dominant 34	ER-Golgi	CERT1 (gain of function)	lipid transfer
ACBD5 Deficiency	ER-peroxisome	ACBD5	trigger; lipid imbalance (plasmalogens); organelle morphology

Grouping and MONDO proposal

kb/groupings/Membrane_Contact_Site_Disorders.yaml lists the conforming entries above under a NECESSARY module-conformance criterion. The class is proposed for MONDO's mechanism branch as proposal 11 in docs/reports/mondo-mechanism-classification-proposal-round-2-2026-10-23.md.

Candidates not yet conformed

Each needs a reading of the entry before a conforms_to is added:

[ ] Charcot-Marie-Tooth Disease: MFN2 tethers the ER to mitochondria, but the entry has no node for the tethering defect itself, only an AAV9 treatment that restores contacts.
[ ] Hereditary Spastic Paraplegia: the SPG87 (TMEM63C) contact-site node already conforms to corticospinal_tract_axonopathy, and conforms_to takes one value. Decide which module it belongs to, or split the node.
[ ] PACS2-Related Developmental and Epileptic Encephalopathy: the entry treats ER-mitochondria contact loss as a hypothesis, not a node.
[ ] Cohen Syndrome (VPS13B, Golgi), Parkinsons Disease (VPS13C), Optic Atrophy 14 (mitochondria-lysosome), SCAR10 (TMEM16K, ER-endosome), Peroxisome Biogenesis Disorder (peroxisome crosstalk node).

Curation gaps

[x] ACBD5 deficiency (retinal dystrophy with leukodystrophy) curated as ACBD5_Deficiency, bound to MONDO:0100112 with MONDO:0030026 mapped as an exact match (ClinGen lumped the two). Both stubs removed. The entry keeps the VLCFA-capture and tether functions of ACBD5 as separate branches, and its knowledge-gap discussion proposes separation-of-function alleles in patient iPSC-derived neural cells.
[ ] Queued stub with a contact-site gene: Alkuraya-Kucinskas_Syndrome (BLTP1). Two stubs with similar names are not contact-site diseases: Cohen-Gibson_Syndrome is caused by EED (PRC2 chromatin), unlike Cohen syndrome (VPS13B), and Chorea_Childhood-onset_With_Psychomotor_Retardation by GPR88, a G-protein-coupled receptor.
[ ] Tether and transfer genes with no entry: ESYT1-3, STARD3, RMDN3 (PTPIP51), ATG2A, MIGA2, GRAMD1A-C, SNX13. Check whether each has a Mendelian disease before nominating a stub.
[ ] GO contact-site cellular components are rarely bound. Only GO:0044232, GO:0044233 and GO:0140268 appear in the KB, and none of the ER-lipid droplet, ER-Golgi, ER-endosome, mitochondria-lysosome or ER-peroxisome contact terms.
[ ] Lipodystrophy genes (BSCL2/seipin, CIDEC) act at ER-lipid droplet contacts but are not described that way.

Cardiomyocytes and Golgi-mitochondria communication

Cardiomyocyte differentiation needs mitochondrial fusion (PMID:24091702) and MFN2-dependent sarcoplasmic reticulum-mitochondria calcium coupling through GRP75 (PMID:41848670). Golgi-derived vesicles carrying PI(4)P or PI(3,4)P2 act at ER-mitochondria and mitofusin-marked sites to finish mitochondrial division or drive fusion (PMID:32193326, PMID:42848893), and deleting the PI(3,4)P2 kinases in mouse cardiomyocytes causes heart failure. Stable direct Golgi-mitochondria contacts are documented only in pancreatic acinar cells (PMID:15722348). The module records this as a knowledge gap with a proposed organelle-signature time course across iPSC-cardiomyocyte differentiation.

[ ] Find a human disorder with a cardiac contact-site node to conform here (candidates: MFN2-related disease with cardiomyopathy, mitochondrial cardiomyopathies with documented MAM loss).

Methods: organelle signature analysis

The Cohen lab (UNC) images six to eight organelles at once in live cells and quantifies their number, volume, position and pairwise and higher-order contacts, an "organelle signature". Applied to primary neurons and astrocytes (PMID:40956669) and to human iPSCs differentiating into neurons (PMID:41726917, preprint), it shows that the organelle profile is cell-type and stage specific, and that ER-peroxisome contacts support plasmalogen synthesis and synapse formation. It measures the contact and morphology nodes together, so the module's knowledge-gap discussion proposes it for patient-derived neurons and astrocytes across several conforming disorders.

Key references: PMID:28538724 (the organelle interactome), PMID:39440475 (imaging contacts review), PMID:38327561 (Contact-FP probes), PMID:31732717 and PMID:30894536 (field reviews and definitions), PMID:28108524 and PMID:28108526 (ACBD5-VAP tether).