MFF

Summary

MFF (mitochondrial fission factor, HGNC:24858) is a protein-coding gene on chromosome 2q36.3, encoding Mitochondrial fission factor (Q9GZY8). Plays a role in mitochondrial and peroxisomal fission.

This is a nuclear gene encoding a protein that functions in mitochondrial and peroxisomal fission. The encoded protein recruits dynamin-1-like protein (DNM1L) to mitochondria. There are multiple pseudogenes for this gene on chromosomes 1, 5, and X. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 56947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): encephalopathy due to defective mitochondrial and peroxisomal fission 2 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 219 total — 6 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_001277062

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24858
Approved symbol	MFF
Name	mitochondrial fission factor
Location	2q36.3
Locus type	gene with protein product
Status	Approved
Aliases	GL004
Ensembl gene	ENSG00000168958
Ensembl biotype	protein_coding
OMIM	614785
Entrez	56947

Gene structure

Transcript identifiers

Ensembl transcripts: 101 — 93 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000304593, ENST00000337110, ENST00000349901, ENST00000353339, ENST00000354503, ENST00000392059, ENST00000409565, ENST00000409616, ENST00000418961, ENST00000423098, ENST00000436237, ENST00000436791, ENST00000443428, ENST00000452930, ENST00000456345, ENST00000460756, ENST00000470090, ENST00000476262, ENST00000476924, ENST00000477362, ENST00000489696, ENST00000490857, ENST00000524634, ENST00000525195, ENST00000530359, ENST00000531278, ENST00000534203, ENST00000707109, ENST00000707110, ENST00000707111, ENST00000868599, ENST00000868600, ENST00000868601, ENST00000868602, ENST00000868603, ENST00000868604, ENST00000868605, ENST00000868606, ENST00000868607, ENST00000868608, ENST00000868609, ENST00000868610, ENST00000868611, ENST00000868612, ENST00000868613, ENST00000868614, ENST00000868615, ENST00000868616, ENST00000868617, ENST00000868618, ENST00000868619, ENST00000868620, ENST00000868621, ENST00000868622, ENST00000868623, ENST00000868624, ENST00000868625, ENST00000868626, ENST00000868627, ENST00000868628, ENST00000868629, ENST00000868630, ENST00000868631, ENST00000868632, ENST00000868633, ENST00000868634, ENST00000868635, ENST00000868636, ENST00000935703, ENST00000935704, ENST00000935705, ENST00000935706, ENST00000935707, ENST00000935708, ENST00000935709, ENST00000935710, ENST00000966766, ENST00000966767, ENST00000966768, ENST00000966769, ENST00000966770, ENST00000966771, ENST00000966772, ENST00000966773, ENST00000966774, ENST00000966775, ENST00000966776, ENST00000966777, ENST00000966778, ENST00000966779, ENST00000966780, ENST00000966781, ENST00000966782, ENST00000966783, ENST00000966784, ENST00000966785, ENST00000966786, ENST00000966787, ENST00000966788, ENST00000966789, ENST00000966790

RefSeq mRNA: 9 — MANE Select: NM_001277062 NM_001277061, NM_001277062, NM_001277063, NM_001277064, NM_001277065, NM_001277066, NM_001277067, NM_001277068, NM_020194

CCDS: CCDS2465, CCDS63139, CCDS63140, CCDS63141, CCDS63142, CCDS74662

Canonical transcript exons

ENST00000304593 — 9 exons

Exon	Start	End
ENSE00001134348	227347226	227347384
ENSE00001184084	227328678	227328789
ENSE00003486225	227330626	227330846
ENSE00003557379	227340292	227340380
ENSE00003611545	227332419	227332588
ENSE00003683674	227352514	227352573
ENSE00003790846	227355677	227355761
ENSE00003900144	227356986	227357833
ENSE00003901540	227325251	227325427

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.5847 / max 470.3419, expressed in 1822 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25728	54.3617	1822
25726	0.6877	295
25727	0.5896	344
25730	0.4963	241
25729	0.4398	222
25736	0.3689	34
25733	0.1901	31
25735	0.1366	30
25738	0.1080	28
25734	0.0790	29

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.85	gold quality
left testis	UBERON:0004533	99.24	gold quality
right testis	UBERON:0004534	99.21	gold quality
male germ cell	CL:0000015	98.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.53	gold quality
testis	UBERON:0000473	98.35	gold quality
adult organism	UBERON:0007023	97.89	gold quality
ganglionic eminence	UBERON:0004023	97.38	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.35	gold quality
body of pancreas	UBERON:0001150	97.01	gold quality
spinal cord	UBERON:0002240	96.95	gold quality
metanephros cortex	UBERON:0010533	96.79	gold quality
cortical plate	UBERON:0005343	96.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.72	gold quality
anterior cingulate cortex	UBERON:0009835	96.64	gold quality
prefrontal cortex	UBERON:0000451	96.60	gold quality
cerebellar cortex	UBERON:0002129	96.60	gold quality
cerebellar hemisphere	UBERON:0002245	96.60	gold quality
cingulate cortex	UBERON:0003027	96.57	gold quality
right ovary	UBERON:0002118	96.52	gold quality
descending thoracic aorta	UBERON:0002345	96.51	gold quality
left ovary	UBERON:0002119	96.50	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.50	gold quality
caudate nucleus	UBERON:0001873	96.46	gold quality
popliteal artery	UBERON:0002250	96.46	gold quality
tibial artery	UBERON:0007610	96.46	gold quality
body of uterus	UBERON:0009853	96.46	gold quality
adrenal tissue	UBERON:0018303	96.46	gold quality
ventricular zone	UBERON:0003053	96.44	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.44	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting MFF, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4645-3P	99.76	69.33	993
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-2116-3P	99.74	64.32	889

Literature-anchored findings (GeneRIF, showing 23)

• Mff is a novel component of a conserved membrane fission pathway used for constitutive and induced fission of mitochondria and peroxisomes. (PMID:18353969)
• MFF gene expression is decreased in both classic and follicular variants of papillary thyroid carcinoma. (PMID:21509594)
• PEX11 proteins attract both Mff and human Fis1 (hFis1) to their site of action. (PMID:22595523)
• MFF over-expression results in extensive mitochondrial fragmentation, driving mitochondrial dysfunction. MFF fibroblasts undergo oxidative stress, with increased ROS production, and the onset of autophagy and mitophagy. (PMID:22878233)
• TRAP1 controls mitochondrial fusion/fission balance through Drp1 and Mff expression. (PMID:23284813)
• MiD49 and MiD51 can act independently of Mff and Fis1 in Drp1 recruitment and suggest that they provide specificity to the division of mitochondria. (PMID:23921378)
• Mitochondrial fission factor (MFF) mRNA is a direct target of miR-27, whose ectopic expression decreases MFF expression through binding to its 3’-untranslated region. (PMID:25431021)
• Data show that expression of MFF protein, miR-593-5p and BRCA1 protein correlates with cisplatin sensitivity and survival of tongue squamous cell carcinoma (TSCC). (PMID:25912308)
• loss of Mff results in failure of Parkin translocation and final clearance of damaged mitochondria (PMID:26008206)
• membrane-anchored Mff differentially regulates various Drp1 isoforms. (PMID:26578513)
• We suggest that, even if laboratory findings are not indicative of mitochondrial or peroxisomal dysfunction, the co-occurrence of optic and/or peripheral neuropathy with seizures warrants genetic testing for MFF mutations (PMID:26783368)
• Data show that increasing dynamin-related protein 1 (Drp1) SUMOylation by knocking down SUMO1-sentrin-SMT3 specific protease 3 (SENP3) reduces both Drp1 binding to mitochondrial fission factor protein (Mff) and stress-induced cytochrome c release. (PMID:28262828)
• expressions of TIA-1 and MFF were augmented in the cancerous liver tissues compared to the corresponding non-tumor tissues at mRNA and protein level, while the levels of miR-200a-3p and miR-27a/b were relatively lower in the cancerous liver tissues (PMID:29496454)
• Iron loading promotes mitochondrial fragmentation in mesenchymal stromal cells from myelodysplastic syndrome patients through activation of the AMPK/MFF/Drp1 pathway. (PMID:29725013)
• Results provide evidence that Mff-mediated anchoring of Drp1 on the outer mitochondrial membrane was necessary for mitochondrial motility in primary cortical neurons. Therefore, the Mff-Drp1 interaction is critical for physiological mitochondrial fission, motility, and function in vitro and in vivo. (PMID:30232469)
• We found that the receptors mitochondrial fission factor (Mff) and mitochondrial elongation factor 1/2 (MIEF1/2) interact with and recruit Drp1(pS637) to mitochondria and that elevated Mff or MIEF levels promote Drp1(pS637) accumulation on mitochondria. We also noted that protein kinase A (PKA), which mediates phosphorylation of Drp1 on Ser-637, is partially present on mitochondria and interacts with both MIEFs and Mff (PMID:31533986)
• Study demonstrated that protein isoforms of mitochondrial fission factor (MFF1 and MFF2) were overexpressed in patients with non-small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. (PMID:31582380)
• Mcl-1 inhibits Mff-mediated mitochondrial fragmentation and apoptosis. (PMID:31941601)
• Encephalopathy due to defective mitochondrial and peroxisomal fission 2 caused by a novel MFF gene mutation in a young child. (PMID:32181496)
• Mitochondrial fission factor (MFF) is a critical regulator of peroxisome maturation. (PMID:32224193)
• Mff oligomerization is required for Drp1 activation and synergy with actin filaments during mitochondrial division. (PMID:34347505)
• Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1alpha/Mff regulation in head and neck squamous cell carcinoma. (PMID:34460078)
• Mitochondrial ““dysmorphology”” in variant classification. (PMID:34750646)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mffb	ENSDARG00000039203
danio_rerio	mffa	ENSDARG00000053753
mus_musculus	Mff	ENSMUSG00000026150
rattus_norvegicus	Mff	ENSRNOG00000015428
drosophila_melanogaster	Tango11	FBGN0050404
caenorhabditis_elegans	mff-2	WBGENE00018894

Paralogs (1): (ENSG00000310562)

Protein

Protein identifiers

Mitochondrial fission factor — Q9GZY8 (reviewed: Q9GZY8)

All UniProt accessions (17): Q9GZY8, A0A0A0MS29, A0A9H3ZVE5, A0A9L9PXN3, A0A9L9PY92, A0A9L9PYL0, C9J846, C9JAF1, C9JHF5, C9JI76, C9JU19, E9PK16, E9PKS0, E9PPR7, E9PPW6, E9PQX8, H7C433

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in mitochondrial and peroxisomal fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface. May be involved in regulation of synaptic vesicle membrane dynamics by recruitment of DNM1L to clathrin-containing vesicles.

Subunit / interactions. Homodimer. Interacts with DNM1L. Interacts with C11orf65/MFI; the interaction inhibits MFF interaction with DNM1L.

Subcellular location. Mitochondrion outer membrane. Peroxisome. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle.

Tissue specificity. Highly expressed in heart, kidney, liver, brain, muscle, and stomach.

Disease relevance. Encephalopathy due to defective mitochondrial and peroxisomal fission 2 (EMPF2) [MIM:617086] An autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Tango11 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9GZY8-1	1	yes
Q9GZY8-2	2
Q9GZY8-3	3
Q9GZY8-4	4
Q9GZY8-5	5

RefSeq proteins (9): NP_001263990, NP_001263991, NP_001263992, NP_001263993, NP_001263994, NP_001263995, NP_001263996, NP_001263997, NP_064579 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008518	Mff/Tango-11	Family
IPR039433	Mff-like_dom	Domain

Pfam: PF05644

UniProt features (27 total): modified residue 13, splice variant 5, sequence variant 3, topological domain 2, chain 1, transmembrane region 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZY8-F1	64.74	0.19

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (13): 202, 229, 233, 295, 146, 149, 151, 146, 115, 155, 157, 172, 200

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 208 (showing top): GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_PROTEIN_TARGETING, TGACCTY_ERR1_Q2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_ORGANELLE_FISSION, GATA3_01, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_MITOCHONDRIAL_FISSION, GOBP_REGULATION_OF_MITOCHONDRIAL_FISSION, GOCC_MITOCHONDRIAL_ENVELOPE, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GATA2_01, CAIRO_HEPATOBLASTOMA_UP

GO Biological Process (6): mitochondrial fission (GO:0000266), obsolete protein targeting to mitochondrion (GO:0006626), mitochondrion organization (GO:0007005), peroxisome fission (GO:0016559), positive regulation of mitochondrial fission (GO:0090141), positive regulation of protein targeting to membrane (GO:0090314)

GO Molecular Function (3): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (11): mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), peroxisome (GO:0005777), synaptic vesicle (GO:0008021), mitochondrial membrane (GO:0031966), protein-containing complex (GO:0032991), sperm principal piece (GO:0097228), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
organelle fission	2
cytoplasm	2
mitochondrion organization	1
organelle organization	1
peroxisome organization	1
mitochondrial fission	1
positive regulation of organelle organization	1
positive regulation of developmental process	1
regulation of mitochondrial fission	1
protein targeting to membrane	1
positive regulation of cellular process	1
regulation of protein targeting to membrane	1
positive regulation of establishment of protein localization	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1
mitochondrial membrane	1
organelle outer membrane	1
microbody	1
exocytic vesicle	1
presynapse	1
mitochondrion	1
mitochondrial envelope	1
organelle membrane	1
cellular_component	1
sperm flagellum	1
intracellular anatomical structure	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

2201 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MFF	DNM1L	O00429	998
MFF	DENR	O43583	994
MFF	FIS1	Q9Y3D6	989
MFF	MIEF2	Q96C03	981
MFF	MIEF1	Q9NQG6	963
MFF	MFN1	Q8IWA4	925
MFF	MFN2	O95140	885
MFF	VDAC1	P21796	741
MFF	OPA1	O60313	736
MFF	PEX11A	O75192	710
MFF	PINK1	Q9BXM7	684
MFF	BNIP3	Q12983	683
MFF	DNM1	Q05193	664
MFF	TOMM20	Q15388	662
MFF	GDAP1	Q8TB36	636

IntAct

42 interactions, top by confidence:

A	B	Type	Score
BCL2	BCL2L11	psi-mi:“MI:0914”(association)	0.930
DNM1L	MIEF2	psi-mi:“MI:0914”(association)	0.700
TNFSF14	TMEM11	psi-mi:“MI:0914”(association)	0.670
MFF	DNM1L	psi-mi:“MI:0915”(physical association)	0.640
DNM1L	MFF	psi-mi:“MI:0915”(physical association)	0.640
SLC1A1	AGPAT2	psi-mi:“MI:0914”(association)	0.640
	MFF	psi-mi:“MI:0915”(physical association)	0.560
SPATA19	MTHFR	psi-mi:“MI:0914”(association)	0.530
MFF	MGAT5	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
MFF	MTNR1B	psi-mi:“MI:0915”(physical association)	0.370
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
PRKY	METTL15	psi-mi:“MI:0914”(association)	0.350
AQP9	HGS	psi-mi:“MI:0914”(association)	0.350
TNFSF14	HAX1	psi-mi:“MI:0914”(association)	0.350
ASB14	TOMM40	psi-mi:“MI:0914”(association)	0.350
MTCH1	IPO5	psi-mi:“MI:0914”(association)	0.350
MTCH2	IPO5	psi-mi:“MI:0914”(association)	0.350

BioGRID (217): MFF (Affinity Capture-MS), POTEKP (Affinity Capture-MS), CCDC126 (Affinity Capture-MS), MGAT5 (Affinity Capture-MS), MFF (Affinity Capture-MS), MFF (Two-hybrid), MFF (Affinity Capture-MS), MFF (Affinity Capture-MS), MFF (Affinity Capture-MS), MFF (Proximity Label-MS), MFF (Proximity Label-MS), MFF (Proximity Label-MS), MFF (Proximity Label-MS), MFF (Proximity Label-MS), MFF (Affinity Capture-MS)

ESM2 similar proteins: A0A7P0TBJ1, A0A804C8T0, A2AQ25, A2BE76, A4IIZ9, A6H7A8, B5DF41, E9PSK7, F4HRI2, I6PL68, O60271, P49140, P68943, Q0V989, Q14AM7, Q14CZ0, Q1JPG0, Q28HY5, Q2TBN4, Q4QQM5, Q4V872, Q50H33, Q58A65, Q5DTY9, Q5EY87, Q5R595, Q5RAR8, Q5RHQ8, Q5RKN3, Q61909, Q62739, Q68DU8, Q6PAX8, Q6PCP5, Q7SZQ4, Q80U23, Q8CID0, Q8NAN2, Q8QFP1, Q91Y53

Diamond homologs: Q3ZCD8, Q4KM98, Q503U3, Q5R795, Q6DD53, Q6GQI8, Q6PCP5, Q7SZQ4, Q969F0, Q9GZY8, Q961C9

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
AMPK	“up-regulates activity”	MFF	phosphorylation
PRKAA1	“up-regulates activity”	MFF	phosphorylation
MFF	“up-regulates activity”	DNM1L	relocalization
MFF	up-regulates	Mitochondrial_fission
PRKD1	“up-regulates activity”	MFF	phosphorylation
PRKD3	“up-regulates activity”	MFF	phosphorylation
PRKD2	“up-regulates activity”	MFF	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

219 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	7
Uncertain significance	91
Likely benign	52
Benign	39

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
253268	NM_001277062.2(MFF):c.106dup (p.Leu36fs)	Pathogenic
253269	NM_001277062.2(MFF):c.739C>T (p.Arg247Ter)	Pathogenic
253270	NM_001277062.2(MFF):c.375_376del (p.Glu127fs)	Pathogenic
2786151	NM_001277062.2(MFF):c.440+2432G>T	Pathogenic
545568	NM_001277062.2(MFF):c.284del (p.Thr95fs)	Pathogenic
996025	NM_001277062.2(MFF):c.355C>T (p.Arg119Ter)	Pathogenic
2180898	NM_001277062.2(MFF):c.181+1_181+2insAAATAATGAAGATGTTTCATTTTCAAGACCAGCAGATCTTGACCT	Likely pathogenic
2799790	NM_001277062.2(MFF):c.-40-842G>A	Likely pathogenic
3065870	NM_001277062.2(MFF):c.-40-841T>G	Likely pathogenic
3065879	NM_001277062.2(MFF):c.-40-842dup	Likely pathogenic
4073431	NM_001277062.2(MFF):c.159del (p.Pro54fs)	Likely pathogenic
4073432	NM_001277062.2(MFF):c.352-2A>C	Likely pathogenic
4689263	NM_001277062.2(MFF):c.-40-842G>T	Likely pathogenic

SpliceAI

1699 predictions. Top by Δscore:

Variant	Effect	Δscore
2:227330624:A:AG	acceptor_gain	1.0000
2:227330624:AG:A	acceptor_gain	1.0000
2:227330625:G:GG	acceptor_gain	1.0000
2:227330625:GG:G	acceptor_gain	1.0000
2:227330625:GGGT:G	acceptor_gain	1.0000
2:227330844:CAG:C	donor_loss	1.0000
2:227332445:A:G	acceptor_gain	1.0000
2:227332584:AAGAA:A	donor_gain	1.0000
2:227332585:AGAA:A	donor_gain	1.0000
2:227332586:GAA:G	donor_gain	1.0000
2:227332586:GAAG:G	donor_gain	1.0000
2:227332587:AA:A	donor_gain	1.0000
2:227332588:AG:A	donor_loss	1.0000
2:227332589:G:C	donor_loss	1.0000
2:227332589:G:GG	donor_gain	1.0000
2:227332590:TAAGT:T	donor_loss	1.0000
2:227332591:AAGTA:A	donor_loss	1.0000
2:227340279:T:TA	acceptor_gain	1.0000
2:227340281:T:TA	acceptor_gain	1.0000
2:227340288:ACAGA:A	acceptor_loss	1.0000
2:227340289:CAG:C	acceptor_loss	1.0000
2:227340290:A:AG	acceptor_gain	1.0000
2:227340291:G:GA	acceptor_gain	1.0000
2:227340291:G:GT	acceptor_loss	1.0000
2:227340291:GAT:G	acceptor_gain	1.0000
2:227340378:TCT:T	donor_gain	1.0000
2:227340381:G:GG	donor_gain	1.0000
2:227347209:T:A	acceptor_gain	1.0000
2:227352486:T:TA	acceptor_gain	1.0000
2:227352499:A:AG	acceptor_gain	1.0000

AlphaMissense

1874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:227357008:T:C	L307P	1.000
2:227356996:T:C	L303P	0.999
2:227330745:T:C	L53S	0.998
2:227357005:G:C	R306P	0.998
2:227357094:A:C	S336R	0.998
2:227357096:C:A	S336R	0.998
2:227357096:C:G	S336R	0.998
2:227330835:T:G	I83S	0.997
2:227355751:T:C	L296P	0.997
2:227357017:T:C	L310P	0.997
2:227357082:T:A	W332R	0.997
2:227357082:T:C	W332R	0.997
2:227330727:T:C	M47T	0.996
2:227330823:T:A	V79D	0.996
2:227330835:T:A	I83N	0.996
2:227355757:G:C	R298P	0.996
2:227356987:T:A	I300K	0.996
2:227357086:T:C	L333P	0.996
2:227330835:T:C	I83T	0.995
2:227355754:G:T	R297I	0.995
2:227357004:C:A	R306S	0.995
2:227330733:T:A	V49D	0.994
2:227356987:T:G	I300R	0.994
2:227357077:C:A	A330D	0.994
2:227357097:T:A	W337R	0.994
2:227357097:T:C	W337R	0.994
2:227355754:G:C	R297T	0.993
2:227355755:A:C	R297S	0.993
2:227355755:A:T	R297S	0.993
2:227357014:T:C	L309P	0.993

dbSNP variants (sampled 300 via entrez): RS1000254563 (2:227325725 C>A,T), RS1000500937 (2:227331699 G>A), RS1000589326 (2:227326996 AGGC>A), RS1000628097 (2:227333005 A>C,G), RS1000803097 (2:227333301 A>G), RS1000835424 (2:227351306 G>C), RS1000856287 (2:227351572 A>C,G), RS1001134789 (2:227344565 G>A), RS1001235265 (2:227344280 A>G,T), RS1001239207 (2:227337613 A>G), RS1001263801 (2:227358167 C>G), RS1001323490 (2:227358152 C>A), RS1001388696 (2:227330988 T>A,C), RS1001418849 (2:227344880 G>A), RS1001460882 (2:227338847 A>C)

Disease associations

OMIM: gene MIM:614785 | disease phenotypes: MIM:617086

GenCC curated gene-disease

Disease	Classification	Inheritance
encephalopathy due to defective mitochondrial and peroxisomal fission 2	Definitive	Autosomal recessive
encephalopathy due to mitochondrial and peroxisomal fission defect	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
encephalopathy due to mitochondrial and peroxisomal fission defect	Moderate	AR
Leigh syndrome	Moderate	AR

Mondo (4): encephalopathy due to defective mitochondrial and peroxisomal fission 2 (MONDO:0014905), mitochondrial encephalomyopathy (MONDO:0004675), microcephaly (MONDO:0001149), encephalopathy due to mitochondrial and peroxisomal fission defect (MONDO:0054865)

Orphanet (1): MFF-related encephalopathy due to mitochondrial and peroxisomal fission defect (Orphanet:485421)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000543	Optic disc pallor
HP:0000544	External ophthalmoplegia
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000758	Abnormal nonverbal communicative behavior
HP:0000762	Decreased nerve conduction velocity
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001324	Muscle weakness
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001510	Growth delay
HP:0002015	Dysphagia
HP:0002353	EEG abnormality
HP:0002376	Developmental regression
HP:0002521	Hypsarrhythmia
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0003819	Death in childhood
HP:0004302	Functional motor deficit
HP:0005484	Secondary microcephaly
HP:0008936	Axial hypotonia
HP:0009830	Peripheral neuropathy

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005580_62	Intraocular pressure	4.000000e-12
GCST007158_8	Refractive astigmatism	1.000000e-06
GCST007160_2	Refractive astigmatism	6.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D017237	Mitochondrial Encephalomyopathies	C05.651.460.620; C10.228.140.163.540; C10.668.491.500.500; C18.452.132.540; C18.452.660.560.620

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases expression, decreases reaction	3
Benzo(a)pyrene	affects methylation, decreases expression	2
Doxorubicin	increases expression, increases reaction, decreases reaction, decreases expression	2
Melatonin	decreases reaction, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases reaction, decreases expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	increases expression, increases abundance	1
perfluorooctanoic acid	increases expression	1
coumarin	decreases phosphorylation	1
3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate	affects cotreatment, decreases reaction, increases expression	1
bavachin	increases expression	1
bisphenol B	increases expression	1
bisphenol S	affects expression	1
3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone	decreases reaction, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Aconitine	increases phosphorylation	1
Arsenic	increases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Calcifediol	increases expression, decreases reaction	1
Deferoxamine	increases expression, affects cotreatment, decreases reaction	1
Dexamethasone	affects cotreatment, decreases expression	1
Glucose	decreases reaction, affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2C1	HAP1 MFF (-) 2	Cancer cell line	Male
CVCL_E2C2	HAP1 MFF (-) 3	Cancer cell line	Male
CVCL_E2C3	HAP1 MFF (-) 4	Cancer cell line	Male
CVCL_XQ47	HAP1 MFF (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

23 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06213090	Not specified	RECRUITING	Patterns of Neurodevelopmental Disorders
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.