Optic atrophy 14 (OPA14) is a dominantly inherited optic neuropathy caused by heterozygous missense variants in MIEF1, which encodes MID51 - an outer mitochondrial membrane protein that recruits the fission GTPase DRP1 to the organelle. It sits in the same axis as the other dominant optic atrophies: OPA1, MFN2 and OPA3 act on mitochondrial fusion, DNM1L on fission, and MIEF1 on the adaptor layer that decides where and when DRP1 acts. What unites them is not fission or fusion in particular but the *regulation* of the balance, and the retinal ganglion cell's apparent inability to tolerate its loss in either direction. The molecular result is unusually specific and is worth stating as a set of negatives. The two disease variants do not stop MID51 reaching the outer mitochondrial membrane, and they do not stop it oligomerising - the two things a missense variant in a membrane adaptor might most obviously be expected to do. What they do is abolish MID51's effect on the network: expressing wild-type MID51 increases mitochondrial fusion events, and expressing either mutant does not. Independent work locates the lesion one step further in, showing that the p.Y240N variant sits in the DRP1-binding loop, disrupts DRP1 recruitment while leaving MID51-Fis1 oligomerisation intact, and selectively inhibits DRP1 GTP hydrolysis - and, in the same experiments, leaves the mitochondria-lysosome contact pathway that MID51 also governs entirely alone. Clinically it is an outlier among the dominant optic atrophies in three respects that the defining paper sets out deliberately: onset in adulthood rather than in the first two decades, a sudden painless loss of acuity that looks like Leber hereditary optic neuropathy rather than the insidious decline of OPA1 disease, and - most distinctively - visual field loss that starts at the periphery and moves inward, the reverse of every other inherited optic neuropathy. The evidence base is two women, aged 55 and 47, from one French cohort of 200, with no reported family segregation and functional support from transient overexpression in HeLa cells. That is thin for a gene-disease assertion, and the entry says so rather than writing around it.
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Conditions with similar clinical presentations that must be differentiated from Optic Atrophy 14:
name: Optic Atrophy 14
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: Optic atrophy 14
term:
id: MONDO:0957824
label: optic atrophy 14
description: >-
Optic atrophy 14 (OPA14) is a dominantly inherited optic neuropathy caused by
heterozygous missense variants in MIEF1, which encodes MID51 - an outer
mitochondrial membrane protein that recruits the fission GTPase DRP1 to the
organelle. It sits in the same axis as the other dominant optic atrophies:
OPA1, MFN2 and OPA3 act on mitochondrial fusion, DNM1L on fission, and MIEF1 on
the adaptor layer that decides where and when DRP1 acts. What unites them is
not fission or fusion in particular but the *regulation* of the balance, and
the retinal ganglion cell's apparent inability to tolerate its loss in either
direction.
The molecular result is unusually specific and is worth stating as a set of
negatives. The two disease variants do not stop MID51 reaching the outer
mitochondrial membrane, and they do not stop it oligomerising - the two things
a missense variant in a membrane adaptor might most obviously be expected to
do. What they do is abolish MID51's effect on the network: expressing wild-type
MID51 increases mitochondrial fusion events, and expressing either mutant does
not. Independent work locates the lesion one step further in, showing that the
p.Y240N variant sits in the DRP1-binding loop, disrupts DRP1 recruitment while
leaving MID51-Fis1 oligomerisation intact, and selectively inhibits DRP1 GTP
hydrolysis - and, in the same experiments, leaves the mitochondria-lysosome
contact pathway that MID51 also governs entirely alone.
Clinically it is an outlier among the dominant optic atrophies in three
respects that the defining paper sets out deliberately: onset in adulthood
rather than in the first two decades, a sudden painless loss of acuity that
looks like Leber hereditary optic neuropathy rather than the insidious decline
of OPA1 disease, and - most distinctively - visual field loss that starts at
the periphery and moves inward, the reverse of every other inherited optic
neuropathy.
The evidence base is two women, aged 55 and 47, from one French cohort of 200,
with no reported family segregation and functional support from transient
overexpression in HeLa cells. That is thin for a gene-disease assertion, and
the entry says so rather than writing around it.
parents:
- hereditary disease
- Mitochondrial Disease
synonyms:
- OPA14
- MIEF1-related optic neuropathy
- MID51-related dominant optic atrophy
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
notes: >-
An inherited optic neuropathy - a neurodegenerative disease of the retinal
ganglion cell and its axon.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
A Mendelian disorder identified by targeted sequencing.
mechanistic_category:
- classification_value: mitochondrial disease
notes: >-
Assigned on the mitochondrial-dynamics mechanism rather than on a
respiratory-chain defect: no bioenergetic abnormality has been measured in
this disease.
references:
- reference: PMID:33632269
title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
- reference: PMID:36044022
title: "Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics."
- reference: PMID:27660309
title: "The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease."
- reference: PMID:36317462
title: "The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands."
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Both reported patients are heterozygous for a MIEF1 missense variant, and the
disease is described throughout the defining paper as dominant.
What that rests on should be stated plainly, because it is not a segregation
analysis. The two patients are unrelated women ascertained separately from a
200-person cohort; no affected relative, no pedigree and no transmission is
described in the accessible text. Dominance is inferred from heterozygosity
plus rarity plus an in vitro functional effect - which is a reasonable
inference and is not the same as a demonstration. The gene-disease validity
question this raises is an open discussion below.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using targeted sequencing of genes involved in mitochondrial dynamics, we
report the first heterozygous variants in MIEF1 linked to disease, which
cause an unusual form of late-onset progressive optic neuropathy
characterized by the initial loss of peripheral visual fields.
explanation: >-
Establishes heterozygosity and the dominant framing of the entity.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In addition, SNP array analyses revealed no chromosomal abnormality, no
copy number variation and no large region of homozygosity that might have
indicated a consanguinity.
explanation: >-
Graded PARTIAL: it excludes a recessive explanation by consanguinity, which
supports the dominant model indirectly, but it is not segregation evidence
and no segregation is reported.
pathophysiology:
- name: Heterozygous MIEF1 Missense Variant
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: PROVISIONAL
description: >-
Two variants, one per patient. c.718T>A gives p.Y240N, which lies in MID51's
DRP1-binding region; c.436C>T gives p.R146W, in a domain conserved with MID49
but of no known function. Neither is in the transmembrane domain that anchors
MID51 in the outer membrane, and neither is at a residue previously shown to
mediate oligomerisation - which is what makes the functional results below
interpretable rather than merely negative.
Marked PROVISIONAL rather than ESTABLISHED because the pathogenicity argument
is rarity plus in silico prediction plus an in vitro effect, in two unrelated
singletons. The p.Y240N variant is absent from databases; p.R146W is
rs778124994 at a gnomAD frequency of about 2 in 100,000, which is rare but
not private.
genes:
- preferred_term: MIEF1
term:
id: hgnc:25979
label: MIEF1
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
zygosity: HETEROZYGOUS
variant_origin: GERMLINE
description: >-
Curated as LOSS_OF_FUNCTION, and the choice needs its reasoning stated
because the alternatives are live. The measured effect is that the mutants
fail to do what wild-type MID51 does - wild-type expression increases
fusion events, mutant expression does not - which is loss of a normal
activity, and the follow-up work attributes it specifically to loss of DRP1
recruitment. DOMINANT_NEGATIVE is the obvious competing hypothesis for a
heterozygous missense variant in an oligomeric adaptor, and it has not been
excluded: no experiment reported here tests the mutant against wild-type
MID51 in the same cell, and the assays are transient overexpression rather
than expression from the endogenous locus. If a dominant-negative
mechanism is later demonstrated, this slot should change.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These variants lead to the p.Y240N and the p.R146W amino-acid changes in
MID51, respectively, with p.Y240N located in a DRP1 binding domain, and
p.R146W located in another domain conserved within MID49, but without known
function
explanation: >-
Names both variants and locates them on the protein, which is what the
mechanism below turns on.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In contrast, neither disease-linked mutations (p.Y240N or p.R146W) are
located in MID51's transmembrane domain which mediates its outer
mitochondrial membrane localization (residues 1 to 48)
explanation: >-
Establishes that the variants are positioned to spare localisation, which
is what the experiments then confirm. The quote stops at the bracketed
citation marker; the same sentence continues to make the equivalent point
about the oligomerisation residues.
downstream:
- target: Preserved MID51 Localisation and Oligomerisation
causal_link_type: DIRECT
- target: Impaired DRP1 Recruitment to the Outer Mitochondrial Membrane
causal_link_type: DIRECT
- name: Preserved MID51 Localisation and Oligomerisation
biological_scale: MOLECULAR
role: modifier
mechanism_confidence: ESTABLISHED
description: >-
A node that records what the disease is not, because two obvious mechanisms
were tested and excluded, and excluding them is what makes the positive
finding meaningful.
Both mutant proteins localise to the mitochondrial network in live cells just
as wild-type MID51 does, so this is not a mislocalisation disease. Both form
dimers, tetramers and high-molecular-weight species in the same ratios as
wild-type, so it is not an oligomerisation disease either. A curator adding
to this entry should not later attach a mislocalisation or
misassembly mechanism to it without new data; these were looked for and were
not there.
An independent group extended the second of those negatives one step
downstream. MID51's other job, in complex with Fis1, is to drive lysosomal
untethering at mitochondria-lysosome contact sites, and that function depends
on the oligomerisation interface rather than on DRP1 binding. The
optic-atrophy variant p.Y240N leaves it intact: it still forms a
Mid51/Fis1 complex and does not misregulate lysosomal untethering or
lysosomal network dynamics. So the preservation established here is not an
incidental in vitro observation - it has a measurable functional consequence,
and it is what makes the disease's lesion specific rather than general.
Whether that specificity explains why the disease is confined to the optic
nerve is an open question below.
cellular_components:
- preferred_term: mitochondrial outer membrane
term:
id: GO:0005741
label: mitochondrial outer membrane
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
This was also true for mutant MID51 p.Y240N and p.R146W proteins, which
also localized to the mitochondrial network in live cells (Fig. 3a, b),
demonstrating that these MIEF1 missense variants linked to optic neuropathy
do not alter MID51's mitochondrial localization.
explanation: >-
Directly supports this node as it is named - localisation is preserved.
The excluded hypothesis is mislocalisation, and it is excluded by this
result being positive for preservation rather than by a REFUTE grading;
`supports` is claim-relative and the claim here is the preserved state.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Thus, these MIEF1 missense variants linked to optic neuropathy do not
significantly disrupt the oligomerization of MID51.
explanation: >-
Directly supports this node as it is named - oligomerisation is preserved.
An oligomerisation mechanism is thereby excluded.
- reference: PMID:36044022
reference_title: "Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In contrast, mutant Mid51(Y240N) associated with dominant optic atrophy,
which does not disrupt Mid51/Fis1-coupled oligomerization, does not
misregulate lysosomal untethering events or downstream lysosomal network
dynamics.
explanation: >-
An independent group's confirmation that oligomerisation is preserved, plus
the functional consequence: the Mid51/Fis1-dependent lysosomal arm is
spared. This is what turns the preserved state from an in vitro observation
into a statement about which of MID51's functions the disease actually
damages.
- name: Impaired DRP1 Recruitment to the Outer Mitochondrial Membrane
biological_scale: MOLECULAR
role: central_effector
mechanism_confidence: PROVISIONAL
description: >-
The proposed molecular lesion. MID51's job is to recruit DRP1, a
dynamin-related GTPase that has no membrane-binding domain of its own, onto
the outer mitochondrial membrane so that it can constrict and divide the
organelle. The p.Y240 residue sits in the loop that binds DRP1, and
independent work concludes that the p.Y240N variant disrupts DRP1 recruitment
while leaving MID51 oligomerisation intact, with the downstream consequence
of selectively inhibiting DRP1 GTP hydrolysis.
Marked PROVISIONAL for a specific reason, not as a general hedge. The DRP1
recruitment claim is well evidenced for p.Y240N, whose position in the
binding loop predicts it. It is *not* evidenced for p.R146W, which lies in a
domain of unknown function outside the DRP1-binding region, and for which no
DRP1 experiment has been reported. Both variants produce the same network
phenotype at the node below, so either p.R146W reaches it by the same route
for a reason nobody has identified, or the two alleles converge from
different molecular starting points. Nothing published distinguishes these.
molecular_functions:
- preferred_term: DRP1 recruitment activity of MID51
term:
id: GO:0030674
label: protein-macromolecule adaptor activity
modifier: DECREASED
biological_processes:
- preferred_term: mitochondrial fission
term:
id: GO:0000266
label: mitochondrial fission
modifier: DYSREGULATED
evidence:
- reference: PMID:36044022
reference_title: "Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Mid51(Y240N) Drp1-binding domain mutant which is linked to dominant optic
atrophy disrupts Drp1 recruitment but not Mid51 oligomerization, leading to
the selective inhibition of Drp1 GTP hydrolysis
explanation: >-
The specific molecular claim of this node, from an independent laboratory
studying the same variant.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Our findings that Mid51 optic neuropathy-linked variants disrupt
mitochondrial fission/fusion dynamics but not its localization or
oligomerization are consistent with the fact that p.Y240 is a residue
located in the loop region (residues 238-242) critical for DRP1 binding
explanation: >-
The structural argument that motivates this node. Graded OTHER because it
is the authors' interpretation of prior structural work rather than an
experiment they performed.
downstream:
- target: Disrupted Mitochondrial Network Dynamics
causal_link_type: DIRECT
- name: Disrupted Mitochondrial Network Dynamics
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The measured cellular phenotype, and the strongest evidence in the entity.
Using a photoactivatable matrix probe to count fusion events between
mitochondria in live cells, wild-type MID51 expression increased the rate of
fusion, and both mutants significantly decreased it relative to wild-type.
Read the direction carefully, because it is counterintuitive. MID51 is a
*fission* adaptor, yet overexpressing wild-type MID51 increases *fusion* -
the established explanation being that excess MID51 sequesters DRP1 in an
inactive state on the outer membrane, so the net effect of more adaptor is
less fission. The mutants fail to produce that effect. So what the assay
measures directly is the loss of MID51's ability to modulate the network at
all, not a shift toward either fission or fusion in the patient. The entry
deliberately does not claim that patients' mitochondria are fragmented or
elongated: nobody has looked at a patient's cells.
biological_processes:
- preferred_term: mitochondrial fusion
term:
id: GO:0008053
label: mitochondrial fusion
modifier: DYSREGULATED
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In contrast, both MID51 p.Y240N and p.R146W mutants resulted in
significantly decreased mitochondrial fusion events and disrupted
mitochondrial network dynamics, as compared to wild-type MID51 (Fig. 3j-m).
explanation: >-
The primary quantitative result for both variants.
- reference: PMID:27660309
reference_title: "The role of Drp1 adaptor proteins MiD49 and MiD51 in mitochondrial fission: implications for human disease."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Heterologous MiD overexpression sequesters inactive Drp1 on the OMM,
promoting fusion; conversely, increased endogenous MiD creates focused Drp1
multimers that optimize OMM scission.
explanation: >-
Explains why overexpressing a fission adaptor increases fusion, which is
what makes the assay's direction interpretable. It is also the reason this
node stops short of claiming a network phenotype in patients: the review
states that the overexpression and endogenous situations differ.
downstream:
- target: Retinal Ganglion Cell Degeneration and Optic Nerve Atrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Why disrupted mitochondrial dynamics kills retinal ganglion cells in
particular is the unsolved question of the whole dominant-optic-atrophy
field, not a gap specific to MIEF1. No intermediate step has been
demonstrated for this gene.
- name: Retinal Ganglion Cell Degeneration and Optic Nerve Atrophy
biological_scale: TISSUE
role: outcome
mechanism_confidence: PROVISIONAL
description: >-
The clinical endpoint. Both patients had pale, moderately excavated optic
disks with a normal retina, strongly abnormal visual evoked potentials, and -
in the patient who had optical coherence tomography - retinal nerve fibre
layer collapse in all quadrants of both eyes. The retinal nerve fibre layer
is the retinal ganglion cell axon layer, so its loss is the closest available
measurement of the cellular claim in this node's title.
Marked PROVISIONAL because ganglion cell death itself is inferred, not
observed: no tissue from a MIEF1 patient has been examined. What is observed
is optic disc pallor plus axon-layer thinning plus conduction failure, which
is the standard clinical basis for inferring ganglion cell loss in the
inherited optic neuropathies.
cell_types:
- preferred_term: retinal ganglion cell
term:
id: CL:0000740
label: retinal ganglion cell
locations:
- preferred_term: optic nerve
term:
id: UBERON:0000941
label: cranial nerve II
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At fundus examination, both individuals had normal retina, but presented
pale and moderately excavated optic disks (Fig. 1a).
explanation: >-
The optic nerve finding, with a normal retina excluding a retinal
dystrophy.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OCT (optical coherence tomography) examination revealed collapsed RNFL
(retinal nerve fiber layer) in all quadrants in both eyes (Fig. 1c).
explanation: >-
Axon-layer loss, the measurable correlate of retinal ganglion cell
degeneration.
phenotypes:
- category: Ophthalmological
name: Optic Atrophy
description: >-
Late-onset, progressive and bilateral, presenting in the fifth and sixth
decades rather than in childhood. Both patients progressed to poor vision.
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
clinical_course: PROGRESSIVE
onset:
onset_category: MIDDLE_AGE
min_age_years: 47
max_age_years: 55
notes: >-
The two reported patients were 55 and 47 at the time of study, and both
first came to ophthalmological attention in adulthood. The paper's own
first discriminating criterion is that "the visual loss was noticed
during adulthood, rather than during the first two decades, as commonly
observed in other DOA". The ages recorded here are ages at study rather
than ages at onset, which the source does not separate cleanly for
patient 1 - she noticed a faint visual problem in 2002 and lost acuity in
2015 - so treat them as bounding the presentation rather than dating it.
On the band chosen, because the paper's own title invites the wrong one.
`MIDDLE_AGE` is HP:0003596 "Middle age onset", which HPO scopes to 40-60
years, and both patients fall inside it. `LATE` is HP:0003584, scoped to
onset after 60, and would be wrong here. The paper is titled "late onset"
in the ordinary sense - late relative to the first two decades, when
other dominant optic atrophies declare themselves - not in HPO's sense.
Do not "correct" this to LATE on the strength of the title.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In both individuals, the disease progressed to poor vision
explanation: >-
The progressive course in both reported patients.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
First, the visual loss was noticed during adulthood, rather than during the
first two decades, as commonly observed in other DOA
explanation: >-
The adult onset that distinguishes this entity from the other dominant
optic atrophies, and the basis for the structured onset above.
- category: Ophthalmological
name: Optic Disc Pallor
phenotype_term:
preferred_term: Optic disc pallor
term:
id: HP:0000543
label: Optic disc pallor
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At fundus examination, both individuals had normal retina, but presented
pale and moderately excavated optic disks (Fig. 1a).
explanation: >-
Disc pallor in both patients.
- category: Ophthalmological
name: Retinal Nerve Fiber Layer Thinning
description: >-
Optical coherence tomography in the second patient showed the retinal nerve
fibre layer collapsed in all quadrants of both eyes. The retinal nerve fibre
layer is the retinal ganglion cell axon layer, so this is the closest
available structural measurement of the cell loss the disease is presumed to
cause - and the reason the pathophysiology node above can name ganglion cells
at all. Reported in one of the two patients, because only one had OCT.
phenotype_term:
preferred_term: Retinal nerve fiber layer thinning
term:
id: HP:0020119
label: Abnormal retinal nerve fiber layer morphology
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
OCT (optical coherence tomography) examination revealed collapsed RNFL
(retinal nerve fiber layer) in all quadrants in both eyes (Fig. 1c).
explanation: >-
The OCT finding in patient 2.
- category: Ophthalmological
name: Peripheral Visual Field Loss Preceding Central Loss
description: >-
The most distinctive feature of this entity, and the one the defining paper
presents as discriminating. In every other inherited optic neuropathy the
field defect begins centrally and spreads outward; here it began at the
periphery and moved inward, sparing some central acuity even late. That is a
testable clinical marker, and it is the reason the authors recommend
screening MIEF1 specifically in patients with severe peripheral field
alteration.
phenotype_term:
preferred_term: Constriction of peripheral visual field
term:
id: HP:0001133
label: Constriction of peripheral visual field
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Thirdly, both cases examined here showed that the disease progressed from
the peripheral to the central visual field, still preserving some visual
acuity in the left eye of the first patient. This is in contrast with all
the reports of ION cases, in which the alteration of the visual field
occurs and evolves from the center to the periphery.
explanation: >-
States both the finding and the contrast with every other inherited optic
neuropathy, which is what makes it discriminating.
- category: Ophthalmological
name: Reduced Visual Acuity
description: >-
Sudden and painless in both patients, without the optic disc elevation or
oedema seen in other autosomal optic neuropathies - a presentation that
resembles Leber hereditary optic neuropathy and is a route to
misdiagnosis.
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
temporality: ACUTE
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Secondly, both patients complained of a rather sudden painless loss of
visual acuity, similar to those observed in maternally inherited LHON,
although without optic disk elevation or edema, which is distinct from what
is generally observed for other autosomal optic neuropathies
explanation: >-
The character and tempo of the acuity loss, and the LHON resemblance.
- category: Ophthalmological
name: Abnormal Visual Evoked Potentials
description: >-
Strongly abnormal in both patients, with normal scotopic and photopic
electroretinograms in the first - the electrophysiological pairing that
places the lesion in the ganglion cell and its axon rather than in the outer
retina.
phenotype_term:
preferred_term: Abnormality of visual evoked potentials
term:
id: HP:0000649
label: Abnormality of visual evoked potentials
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Visual evoked potentials were strongly affected for both eyes, while
scotopic and photopic electroretinograms (ERGs) were normal.
explanation: >-
Abnormal conduction with preserved outer-retinal function, localising the
lesion.
genetic:
- name: MIEF1
gene_term:
preferred_term: MIEF1
term:
id: hgnc:25979
label: MIEF1
relationship_type: CAUSATIVE
variant_origin: GERMLINE
presence: PRESENT
notes: >-
MIEF1 encodes MID51, also written MiD51; the gene is sometimes referred to by
the protein name, and its paralogue MIEF2 encodes MID49. Only two disease
alleles are known: c.718T>A p.(Tyr240Asn), absent from databases, in exon 6;
and c.436C>T p.(Arg146Trp), rs778124994, in exon 5, at a gnomAD frequency of
1.99e-5.
A transcription error in the source, flagged so it is not propagated. The
figure legend describing the second variant states that c.436C>T is
"localized at position 416 of the MID51 protein" while naming the change
p.R146W in the same sentence; 146 is the position consistent with the
nucleotide change, the sequence alignment, and every other mention in the
paper. Read 416 as a typographical error for 146.
What is not known about this gene's variants. There is no reported MIEF1
variant that is *not* disease-associated in a patient with optic neuropathy,
no missense-constraint analysis, and no second family - so a new MIEF1
missense variant found in a patient with optic atrophy has essentially no
gene-specific precedent to be interpreted against, beyond whether it falls in
the DRP1-binding loop.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The first individual harbored a c.718 T > A variant, not referenced in any
database, and the second individual harbored a c.436C > T variant, referred
to as rs778124994, with a frequency of 1.99e-5 in GnomAD database.
explanation: >-
The two alleles and their population frequencies.
- reference: PMID:36044022
reference_title: "Mid51/Fis1 mitochondrial oligomerization complex drives lysosomal untethering and network dynamics."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Mid51(Y240N), located in its Drp1-binding domain, was linked to dominant
optic atrophy
explanation: >-
A second group's independent statement of the variant's domain assignment.
Graded OTHER rather than IN_VITRO because the sentence is background
framing in that paper's introduction rather than a result it reports.
prevalence:
- population: French inherited optic neuropathy cohort
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Two patients, both women, from a cohort of 200 individuals in France with
inherited optic neuropathy who had already been screened negative for OPA1,
OPA3, WFS1 and the three primary LHON mitochondrial-DNA mutations. No further
MIEF1 patient has been published.
The fraction - two of two hundred, or one percent - is a diagnostic yield
within an already-selected undiagnosed cohort, not a prevalence and not the
share of inherited optic neuropathy attributable to MIEF1. The cohort was
enriched for cases that the common genes had failed to explain, which inflates
any rare gene's apparent share, and the panel covered only 22 genes, which
means an unknown fraction of those 200 remain undiagnosed for reasons the
study could not see.
A larger unselected series from the same French diagnostic service puts an
upper bound on the gene's importance. Sequencing 87 nuclear genes plus the
Leber mitochondrial-DNA mutations in 2,186 probands referred for suspected
hereditary optic neuropathy reached a diagnosis in 30 percent, and ten genes
accounted for more than 96 percent of those diagnoses. MIEF1 is not among
those ten. Eleven further genes, each under one percent of cases, together
explained 17 individuals in the whole series - so whatever share MIEF1 holds
lies inside that residue.
Note what this does *not* add: patients. The 2023 series comes from the same
Angers reference centre and shares five authors with the 2021 MIEF1 report,
including its first author, so any MIEF1 case within it is presumptively one
of the two already reported rather than a new one. This entry counts two
patients in total.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two hundred individuals in France affected by an ION were included in this
study. None of the individuals included had a molecular diagnosis after
screening for pathogenic variants in OPA1, OPA3 and WFS1 exonic sequences
and LHON-associated mtDNA mutations.
explanation: >-
The cohort and its prior-exclusion criteria, which is what makes the
two-in-two-hundred figure a yield rather than a prevalence.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we identified two individuals (Fig. 1) harboring a MIEF1 heterozygous
variant, which were confirmed by Sanger sequencing
explanation: >-
The two patients found.
- reference: PMID:36317462
reference_title: "The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The identified top 10 nuclear genes included OPA1, WFS1, ACO2, SPG7, MFN2,
AFG3L2, RTN4IP1, TMEM126A, NR2F1 and FDXR.
explanation: >-
MIEF1 is absent from the ten genes that account for more than 96 percent of
nuclear hereditary optic neuropathy diagnoses in a 2,186-proband series,
which bounds how common it can be.
- reference: PMID:36317462
reference_title: "The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Eleven additional genes, each accounting for less than 1% of cases, were
identified in 17 individuals.
explanation: >-
Quantifies the residue outside the top ten - 17 individuals across eleven
genes - which is the population any MIEF1 share must come from. The
abstract does not name those eleven genes, so this entry does not assert
that MIEF1 is one of them.
experimental_models:
- name: MID51 variant expression in HeLa cells
experimental_model_type: CELL_LINE
description: >-
Transient expression of mCherry- or myc-tagged wild-type, p.Y240N and
p.R146W MID51 in HeLa cells, assayed by live confocal microscopy for
localisation, by immunoprecipitation and immunoblot for oligomerisation, and
by photoactivatable matrix probe for fusion events. This is the entire
functional evidence base for the disease, and it is the same system in which
the independent group later mapped the DRP1-recruitment defect.
modeled_mechanisms:
- target: Disrupted Mitochondrial Network Dynamics
relationship: RECAPITULATES
fidelity: LOW
description: >-
The assay demonstrates that both patient variants abolish MID51's normal
effect on mitochondrial network dynamics, which is the disease's proposed
cellular lesion.
limitations: >-
Three limitations, and they compound. The cell is a cervical
adenocarcinoma line, not a retinal ganglion cell, and the selective
vulnerability of that neuron is the whole unexplained part of the disease.
The variants are expressed transiently from a plasmid on top of endogenous
wild-type MID51 rather than from the endogenous locus, and the cited review
states explicitly that heterologous overexpression and increased endogenous
MiD have opposite effects on the network - so the assay's baseline is a
condition that does not occur in a patient. And the readout is a
difference from overexpressed wild-type MID51, not from an untransfected
cell, which measures loss of an overexpression artefact's effect rather
than the variant's effect on a normal cell. Fidelity is graded LOW on that
basis.
readouts:
- name: Mitochondrial fusion events after mito-PAGFP photoactivation
target: Disrupted Mitochondrial Network Dynamics
direction: DECREASED
interpretation: >-
Both mutants gave significantly fewer fusion events than wild-type MID51,
which is the quantitative basis for the disease's cellular claim.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In contrast, both MID51 p.Y240N and p.R146W mutants resulted in
significantly decreased mitochondrial fusion events and disrupted
mitochondrial network dynamics, as compared to wild-type MID51 (Fig.
3j-m).
explanation: >-
The fusion-event measurement underlying this readout.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Together, these results show that MIEF1 mutations linked to optic
neuropathy preferentially disrupt the ability of MID51 to regulate
mitochondrial fission/fusion dynamics.
explanation: >-
The authors' conclusion from this model, which is what makes it
informative for this node.
- target: Preserved MID51 Localisation and Oligomerisation
relationship: MEASURES
fidelity: MODERATE
description: >-
The same system was used to test, and exclude, mislocalisation and
oligomerisation defects. Graded MEASURES rather than RECAPITULATES because
the informative result is a negative one: the model establishes that two
candidate mechanisms are absent.
limitations: >-
A negative result in an overexpression system is weaker than a positive
one, because excess wild-type protein could mask a partial folding or
trafficking defect. The oligomerisation assay in particular scores tagged
protein pulled down from a transfected cell, not the endogenous complex.
readouts:
- name: MID51 oligomer to monomer ratio by immunoprecipitation
target: Preserved MID51 Localisation and Oligomerisation
direction: UNCHANGED
interpretation: >-
Mutant and wild-type MID51 formed dimers, tetramers and
high-molecular-weight species in similar ratios - a real negative
result, recorded as such.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similarly, we found that both mutant proteins MID51 p.Y240N (Fig. 3d-f)
and MID51 p.R146W (Fig. 3g-i) also showed similar oligomerization
patterns to wild-type MID51 (Fig. 3c), with similar ratios of each
oligomeric species to monomer levels.
explanation: >-
The oligomerisation measurement underlying this readout.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We next investigated whether MIEF1 variants disrupted the ability of
MID51 to self-oligomerize.
explanation: >-
Establishes that the model was applied to this question, which is what
makes its negative result usable.
diagnosis:
- name: Recognising the Reversed Visual Field Pattern and Sequencing MIEF1
description: >-
The practical content of this entity is a pattern-recognition rule. An adult
with sudden painless bilateral visual loss, pale non-swollen optic discs,
abnormal visual evoked potentials with normal electroretinograms, and a field
defect that started at the *periphery*, who is negative for OPA1, OPA3, WFS1
and the LHON mitochondrial-DNA mutations, is the patient in whom MIEF1 should
be sequenced. The defining paper makes exactly that recommendation.
Two negatives are part of the workup and were done in both reported patients:
glaucoma was excluded, and serology for anti-aquaporin-4 and
anti-myelin-oligodendrocyte-glycoprotein antibodies was negative. Both are important because a sudden
painless optic neuropathy in a middle-aged woman is more often an acquired
inflammatory one than a genetic one.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Together, our work should prompt the molecular screening of MIEF1 in ION
individuals with severe alterations of the peripheral visual field
explanation: >-
The authors' own screening recommendation, which is the diagnostic content
of this entity.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At initial assessments, neither of the two individuals had symptoms or
immunological profiles compatible with Glaucoma, Neuro Myelitis Optica or
myelin oligodendrocyte glycoprotein optic neuritis.
explanation: >-
The acquired causes that were excluded before a genetic diagnosis was
pursued.
differential_diagnoses:
- name: OPA1-related dominant optic atrophy and the other mitochondrial-dynamics optic neuropathies
description: >-
The genes are neighbours in mechanism and separable on presentation. OPA1
accounts for most dominant optic atrophy, with more than 400 pathogenic
variants described, and typically declares itself in the first two decades
with insidious central visual loss. MFN2 and OPA3 act on fusion; SPG7 and
AFG3L2 act indirectly through OPA1 processing; DNM1L acts on fission from the
other side of the balance. MIEF1 is distinguished from all of them by adult
onset, sudden painless acuity loss, and peripheral-first field loss - and, if
those fail, by sequencing.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In dominant optic atrophy (DOA, MIM165500), it is now well established that
mutations in genes involved in mitochondrial dynamics such as OPA1
(MIM#605290) are the main cause of the disease. More than 400 distinct
pathogenic variants have been described in OPA1
explanation: >-
Establishes OPA1 as the dominant-optic-atrophy differential's largest
component.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Interestingly, DNM1L mutations resulting in excessive mitochondrial fusion
have also been identified in patients with a similar ophthalmological
presentation
explanation: >-
Places a fission-side gene in the same clinical territory as the
fusion-side ones.
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
thus providing evidence that alterations of both fusion and fission
compromise retinal ganglion cell survival
explanation: >-
The principle that unites the differential: imbalance in either direction
damages the same neuron, which is why MIEF1 belongs in this list despite
acting on the opposite side from OPA1.
- name: Leber hereditary optic neuropathy
description: >-
The most consequential differential, because MIEF1 disease imitates it. Both
present with sudden painless bilateral visual loss; LHON is maternally
transmitted through mitochondrial-DNA mutations and typically shows optic
disc elevation and peripapillary telangiectasia in the acute phase, which
these patients did not have. Both reported MIEF1 patients had been screened
for the three primary LHON mutations and were negative, which is why they
were in the undiagnosed cohort at all.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Secondly, both patients complained of a rather sudden painless loss of
visual acuity, similar to those observed in maternally inherited LHON,
although without optic disk elevation or edema
explanation: >-
States the resemblance and the one clinical feature that separates them.
- name: Acquired optic neuropathies - glaucoma, neuromyelitis optica, MOG-antibody optic neuritis
description: >-
Not genetic, but the practical differential for an adult presenting this way,
and the one the reported patients were worked up for. Peripheral-first field
loss with excavated discs is also the pattern of glaucoma, which makes normal
intraocular pressure - documented in the second patient - a load-bearing
observation rather than a formality.
evidence:
- reference: PMID:33632269
reference_title: "Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She presented with pale and excavated optic disks (Fig. 1a, right) with
normal intra-ocular pressure (IOP: RE: 9 and LE: 10 mmHg).
explanation: >-
Excavated discs with normal pressure, which is what separates this from
glaucoma.
discussions:
- discussion_id: opa14_gene_disease_validity
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is the MIEF1-optic atrophy association established, and would it survive a
formal gene-disease validity assessment?
attaches_to:
- "genetic#MIEF1"
- "pathophysiology#Heterozygous MIEF1 Missense Variant"
rationale: >-
This is the first thing a reader of this entry should know, and the entry is
written around it rather than despite it.
The whole human evidence base is two unrelated women from one cohort, each
heterozygous for a different missense variant. No affected relative is
described, no segregation is reported, and no second family has been
published in the five years since. One of the two variants, p.R146W, is
rs778124994 and present in gnomAD, and lies in a domain the paper itself
describes as having no known function. Functional support is transient
overexpression in HeLa cells, measured against overexpressed wild-type rather
than against an untransfected baseline.
None of that means the association is wrong. The independent replication of
the p.Y240N DRP1-binding defect by a second laboratory is real support, the
clinical phenotype is genuinely unusual in a way that would be odd to arrive
at by chance, and the gene sits squarely in a pathway whose other members
cause the same disease. It means the association is *provisional*, which is
how the pathophysiology nodes here are graded and why no
treatment or prognosis content is curated.
The concrete thing that would settle it is a second family with segregation,
or a formal ClinGen gene-disease validity curation. Neither exists. Until one
does, a curator should resist the pull to write this entry as though the
entity were secure because it has a MONDO identifier and an OMIM number -
those record that a claim was made, not that it was replicated.
proposed_experiments:
- experiment_id: exp_opa14_second_family
name: Segregation in additional MIEF1 families
description: >-
Screen MIEF1 in inherited-optic-neuropathy cohorts that are unsolved after
OPA1 and mitochondrial-DNA testing, prioritising patients with
peripheral-onset field loss, and test segregation in any family found. Two
informative meioses would do more for this entity than any further cell
biology.
- discussion_id: opa14_hela_overexpression_is_the_whole_model
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Does the loss of MID51's network-modulating effect seen in overexpressing
HeLa cells describe what happens in a heterozygous patient's retinal ganglion
cell?
attaches_to:
- "pathophysiology#Disrupted Mitochondrial Network Dynamics"
- "experimental_models#MID51 variant expression in HeLa cells"
rationale: >-
Curated as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the
experiments exist and are well executed; what is untested is their
relationship to the disease.
The specific mismatch is not just the usual cell-line caveat. The review
cited by this entry states that heterologous MiD overexpression sequesters
inactive DRP1 and promotes fusion, whereas increased *endogenous* MiD
promotes fission - the two conditions have opposite effects on the network.
The assay therefore measures the mutants' failure to reproduce an
overexpression phenotype, in a condition that does not occur in a patient, in
a cervical adenocarcinoma line, against a background of intact endogenous
wild-type MID51. What a patient has is one wild-type and one variant allele
at the endogenous locus in a retinal ganglion cell.
Whether that matters is genuinely open. It is entirely possible that the
variants are simple loss-of-function alleles and the overexpression assay
reads that out faithfully. It is also possible that the heterozygous
phenotype involves the mutant protein interfering with the wild-type one,
which this design cannot see, and which would change
`functional_impact_category` on the trigger node from LOSS_OF_FUNCTION to
DOMINANT_NEGATIVE.
Note also that nothing about the retinal ganglion cell's selective
vulnerability is addressed by any model of this disease. That is a gap shared
with the entire dominant-optic-atrophy field rather than a MIEF1-specific
one, which is why it is stated on the causal edge rather than made a separate
discussion here.
proposed_experiments:
- experiment_id: exp_opa14_knockin_rgc
name: Endogenous-locus MIEF1 variants in human retinal ganglion cells
description: >-
Knock the p.Y240N and p.R146W variants into the endogenous MIEF1 locus of
induced pluripotent stem cells, heterozygously, differentiate to retinal
ganglion cells, and measure mitochondrial morphology, network dynamics,
axonal transport and survival against isogenic controls. Include a
homozygous arm to distinguish haploinsufficiency from a dominant-negative
effect.
- discussion_id: opa14_pathway_selectivity
kind: OPEN_QUESTION
status: OPEN
prompt: >-
Why does the optic-atrophy variant spare the mitochondria-lysosome contact
pathway that MID51 also controls, and does that selectivity explain why the
disease is confined to the optic nerve?
attaches_to:
- "pathophysiology#Impaired DRP1 Recruitment to the Outer Mitochondrial Membrane"
rationale: >-
An unusually clean natural experiment sits inside this gene, and it has not
been followed up.
MID51 has two separable jobs. Through its DRP1-binding loop it recruits DRP1
and drives mitochondrial fission. Through a distinct oligomerisation
interface, in complex with Fis1, it drives lysosomal untethering by way of
Rab7 GTP hydrolysis at mitochondria-lysosome contact sites. The
optic-atrophy variant p.Y240N hits the first and, in direct experiments,
leaves the second untouched - it still forms a complex with Fis1 and does not
misregulate lysosomal tethering. A different variant in the oligomerisation
interface, p.R169W, does the reverse, and has been tentatively linked to
Parkinson's disease rather than to optic atrophy.
So one gene appears to produce two different neurological diseases through
two separable interfaces, with a clean dissociation demonstrated in the same
experiments. If that holds, it is a strong hypothesis for why MIEF1 disease
is confined to the optic nerve rather than being a broader neurodegenerative
syndrome.
Two cautions before it is treated as established. The Parkinson's link for
p.R169W is described in the source as potential rather than demonstrated, so
half the dissociation rests on a tentative clinical association. And the
optic-atrophy arm rests on p.Y240N alone; p.R146W has never been tested in
the lysosomal assays, so it is unknown whether the second optic-atrophy
allele shows the same selectivity.
proposed_experiments:
- experiment_id: exp_opa14_second_allele_lysosomal_assay
name: Test p.R146W in the mitochondria-lysosome contact assays
description: >-
Apply the inter-lysosomal untethering and Rab7 GTP hydrolysis assays to the
second optic-atrophy allele p.R146W, alongside p.Y240N and p.R169W. If
p.R146W also spares the lysosomal arm, the interface-to-disease mapping
becomes a property of the phenotype rather than of one variant.
notes: >-
On conformance, which this entry deliberately does not declare. The obvious
candidate module is `mitochondrial_dysfunction`, and it does not fit: its nodes
are age-related mitochondrial damage and mtDNA mutation, bioenergetic decline
and oxidative stress, impaired mitophagy and quality control, mitochondrial
contribution to senescence and inflammation, and age-related tissue
dysfunction. None of them is about fission-fusion balance, and no bioenergetic,
reactive-oxygen or mitophagy measurement exists for MIEF1, so declaring
conformance to the bioenergetic node would assert an unmeasured claim in order
to gain a link.
What is missing is a mitochondrial-dynamics module. The genes that would
populate it are named in this entry's own differential - OPA1, MFN2, OPA3,
DNM1L, MFF, SPG7, AFG3L2, YME1L1 and MIEF1 - and they converge on one node,
that regulated fission-fusion balance is required for retinal ganglion cell
survival, with the striking property that imbalance in either direction
produces the same disease. Creating that module is a larger piece of work than
a single-disease entry should contain, and it should be created from the OPA1
and DNM1L literature rather than from this two-patient entity. Recorded here so
the absence is a decision rather than an oversight.
On what is not curated. There is no `treatments:` block, no `progression:`
block beyond what the phenotype descriptions carry, and no `animal_models:`
block. No therapy has been reported or trialled for MIEF1 disease, and no
natural history study exists beyond the two individual descriptions.
On the absent `animal_models:` block specifically, since the claim is easy to
overstate. No animal carrying a disease-linked MIEF1 allele has been reported
in any source consulted for this entry. That is narrower than "MIEF1 has no
animal biology": Mid51 is studied in mice and in cultured cells for its
ordinary fission and mitophagy roles, and a search on the gene returns that
work first. None of it involves p.Y240N or p.R146W, so none of it models this
disease, and a curator should not promote a Mid51 mouse paper into this entry
on the strength of the gene name.
The idebenone literature for Leber hereditary optic neuropathy and the general
dominant-optic-atrophy management literature are both close enough to look
importable, and importing either would attribute to two patients an experience
recorded only in people with other genotypes.
On the deep-research report committed with this entry. It was used as a lead
and one of its claims did not survive checking, which is recorded here because
the number is the kind that gets copied. The report states that MIEF1 accounted
for about 1.08 percent of positive optic atrophy diagnoses in the 2,186-proband
series; that series' abstract says the genes outside its top ten each account
for *less than* one percent, and does not name MIEF1 at all. The bound curated
in the prevalence block is the one the abstract supports, not the report's
figure. Its Named Entity Confusion preflight passes cleanly (MIEF1 mentioned 47
times, next gene OPA1 at 3).
On the direction of the cellular phenotype. The measured result is that
wild-type MID51 overexpression increases mitochondrial fusion and the mutants
do not. It is tempting to compress that into "MIEF1 variants cause
mitochondrial fragmentation" or "cause hyperfusion"; neither is supported.
Nothing has been measured in a patient's cells, and the direction of the effect
in the assay is a property of the overexpression system rather than of the
disease. The node states the loss of modulation and stops there.
Optic atrophy 14 (OPA14) is an ultra-rare, apparently autosomal-dominant mitochondrial-dynamics disorder caused by heterozygous variants in MIEF1, encoding the outer-mitochondrial-membrane protein MID51. Its defining phenotype is isolated, late-onset, progressive bilateral optic neuropathy, unusual among inherited optic neuropathies because peripheral visual-field loss precedes or exceeds central loss. The entire disease-defining clinical evidence retrieved traces to two women reported in 2021; consequently, frequencies calculated below describe that two-person series, not reliable population estimates. Open Targets recognizes the MIEF1–OPA14 association but likewise grounds its four evidence records in the same publication, PMID 33632269. (OpenTargets Search: optic atrophy 14-MIEF1, charif2021dominantmutationsin pages 1-3)
The most important verified findings and evidence gaps are summarized here:
| domain | verified finding | quantitative details | evidence type/strength |
|---|---|---|---|
| disease identity | Optic atrophy 14 is a very rare inherited optic neuropathy associated with MIEF1 (MID51); MONDO disease mapping supports the association. | MONDO:0957824; MIEF1 Ensembl ENSG00000100335; Open Targets association score 0.5659 with 4 evidence items tied to PMID 33632269. (OpenTargets Search: optic atrophy 14-MIEF1) | Curated disease-target database + primary human report; moderate for identity, limited by few cases. |
| Patient 1 | Female with late-adult onset, non-syndromic optic neuropathy featuring peripheral visual field loss progressing to central loss, optic disc pallor/excavation, abnormal VEP, normal ERG/retina. | Age 55; origin Maghreb; first noted visual problem in 2002; right-eye BVA 10/20 initially, by 2015 right eye 1/20, left eye 18/20; elevated sedimentation rate 44 mm; no peripheral neuropathy reported. (charif2021dominantmutationsin pages 4-6, charif2021dominantmutationsin pages 3-4) | Primary human case report; strong for phenotype in this individual. |
| Patient 2 | Female with late-adult onset optic neuropathy after cesarean delivery, superior altitudinal/peripheral field loss, optic disc pallor/excavation, macular microcysts, severe RNFL loss, abnormal VEP, normal brain MRI/ENT. | Age 47; born in Egypt; onset 2002, 1 month after cesarean; initial BVA right 3/20, left 10/20; by 2012 right 2/20, left 8/20; by 2015 right hand moving, left 4/20; IOP right 9 mmHg, left 10 mmHg. (charif2021dominantmutationsin pages 4-6, charif2021dominantmutationsin pages 3-4) | Primary human case report; strong for phenotype in this individual. |
| genetics | Two heterozygous missense MIEF1 variants were identified and confirmed by Sanger sequencing; inheritance interpreted as dominant/monoallelic, but familial segregation data were not reported. | Patient 1: c.718T>A, p.Y240N, absent from cited databases; Patient 2: c.436C>T, p.R146W, rs778124994, gnomAD frequency 1.99e-5; variants predicted damaging by SIFT/PolyPhen and disease-causing by MutationTaster. ClinVar records RCV003387453/RCV003387454 released 2023-10-28. (charif2021dominantmutationsin pages 3-4, OpenTargets Search: optic atrophy 14-MIEF1) | Primary human genetics + curated variant database; moderate-high for variant-disease link, limited by n=2 and absent segregation. |
| functional mechanism | Disease-linked MID51 variants do not disrupt mitochondrial localization or oligomerization, but do impair mitochondrial network dynamics/fusion in cell assays; p.Y240N lies in the DRP1-binding region. | Mutant proteins localized to mitochondria similarly to WT; oligomerization pattern retained; mito-PAGFP assays showed significantly reduced fusion versus WT; p.Y240 located in DRP1-binding loop 238-242; MID51 is an outer mitochondrial membrane DRP1 adaptor. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8, atkins2016theroleof pages 1-2, atkins2016theroleof pages 8-9) | Disease-specific in vitro functional evidence + broader mechanistic literature; moderate-high for mechanism, indirect for retinal tissue. |
| epidemiology | Extremely rare cause of hereditary optic neuropathy; no population prevalence or incidence established. | In the original French unsolved ION cohort, 2/200 cases carried MIEF1 variants (1.0%). In a larger 2023 hereditary optic neuropathy dataset, MIEF1 accounted for 2 individuals and ~1.08% of positive optic atrophy diagnoses in the relevant subgroup; overall positive diagnostic rate across 2,186 probands was 30%. (charif2021dominantmutationsin pages 3-4, rocatcher2023thetop10 pages 2-3, rocatcher2023thetop10 pages 1-1) | Cohort-based observational evidence; moderate for rarity within referral cohorts, low for general-population frequency. |
| diagnosis | Current diagnosis relies on ophthalmic phenotyping plus molecular testing after exclusion of more common optic neuropathy causes; expanded gene panels improve detection of rare genes like MIEF1. | In both cases: normal retina, pale moderately excavated optic discs, abnormal VEP; Patient 2 had OCT evidence of RNFL collapse in all quadrants. Negative/normal workup included OPA1/OPA3/WFS1 and primary LHON mtDNA mutations, SNP array (no CNV/chromosomal abnormality/large ROH), anti-NMO and anti-MOG serology in Patient 2, and glaucoma-compatible findings absent at presentation. Initial study panel covered 22 genes with >95% of bases at >100X coverage. (charif2021dominantmutationsin pages 4-6, charif2021dominantmutationsin pages 6-8, rocatcher2023thetop10 pages 2-3) | Primary clinical diagnostic evidence + cohort practice data; high for reported cases. |
| treatment | No disease-specific therapy, clinical trial, or formal management guideline was identified for MIEF1-related optic atrophy; care is supportive. | No treatment response data reported in the two cases. Reviews of inherited optic neuropathies discuss idebenone (approved for LHON in Europe), antioxidants, gene/RNA-based therapies, cysteamine, and NAD+ strategies, but not as established therapy for MIEF1 optic atrophy. (d’esposito2024insightsonthe pages 11-12, d’esposito2024insightsonthe pages 1-2, d’esposito2024insightsonthe pages 12-14) | Direct evidence absent for MIEF1; only low-strength extrapolation from broader optic neuropathy literature. |
| evidence gaps | Major unanswered questions remain on natural history, penetrance, segregation, sex effects, modifier genes, environmental triggers, pathology outside the optic nerve, and translational models. | Only 2 published disease-defining patients were identified in retrieved evidence; no validated prevalence/incidence, no mortality/prognosis statistics, no disease-specific animal/iPSC/omics studies, no preventive factors, and no interventional trials found. (charif2021dominantmutationsin pages 3-4, d’esposito2024insightsonthe pages 12-14) | Strong evidence of knowledge scarcity; conclusions limited by ultra-rare case count. |
Table: This table summarizes the verified evidence base for MIEF1/MID51-related optic atrophy, separating patient-level findings from broader mechanistic and epidemiologic evidence. It is useful for quickly identifying what is established, what is extrapolated, and what remains unknown.
OPA14 is a nonsyndromic inherited optic neuropathy involving retinal ganglion-cell (RGC) degeneration, retinal nerve-fiber-layer (RNFL) loss, optic-disc pallor, visual-field constriction, and progressive visual impairment. The defining authors described it as an “unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields.” This contrasts with the central-to-peripheral field progression typical of most inherited optic neuropathies. (charif2021dominantmutationsin pages 1-3, charif2021dominantmutationsin pages 3-4)
The evidence consists of an aggregated disease-level ontology record linked to a primary, patient-level research cohort—not EHR-derived population data. Open Targets aggregates literature, Genomics England and EVA/ClinVar evidence, but all four association items cited the same human paper. (OpenTargets Search: optic atrophy 14-MIEF1)
The established cause is a germline heterozygous MIEF1 missense variant that perturbs MID51-dependent mitochondrial-network dynamics. Both reported variants were confirmed by Sanger sequencing. A monoallelic autosomal, non-imprinted model is recorded by Open Targets and is biologically consistent with the authors’ designation of dominant disease. However, familial segregation was not reported, so transmission versus de novo occurrence remains unresolved. (charif2021dominantmutationsin pages 3-4, OpenTargets Search: optic atrophy 14-MIEF1)
Two disease-associated variants are known from the defining report:
Both were predicted damaging by SIFT and PolyPhen and disease-causing by MutationTaster. These predictions are supporting—not independently decisive—evidence. Functional assays substantially strengthen causality, but the tiny case count and absent segregation require caution in asserting penetrance or a broad genotype–phenotype relationship. (charif2021dominantmutationsin pages 3-4)
No susceptibility loci, modifier genes, protective alleles, founder variants, anticipation, germline mosaicism, or carrier-frequency estimates have been established. Because this is dominant disease, “carrier” is not clinically equivalent to an unaffected recessive carrier; variant-positive relatives may instead have age-dependent or presently unquantified risk.
No validated toxin, infection, dietary, smoking, alcohol, occupational, sex, or lifestyle risk factor is known. Patient 2 noticed loss one month after cesarean delivery, but a temporal association in one person does not establish pregnancy or surgery as a trigger. Patient 1 had seronegative rheumatoid polyarthritis treated with leflunomide; patient 2 had hypothyroidism, hypercholesterolemia and iron deficiency. Neither pattern was interpreted as causal. (charif2021dominantmutationsin pages 4-6)
No protective environmental factor or demonstrated gene–environment interaction exists. General avoidance of tobacco, excessive alcohol and known mitochondrial/optic-nerve toxins is biologically prudent in mitochondrial optic neuropathy, but this is extrapolation, not OPA14-specific evidence.
Because only two patients are documented, “2/2” means the published series, not an estimated disease frequency.
Patient 1: Maghreb-origin woman, age 55. A faint right-eye problem was noticed in 2002 with best visual acuity (BVA) 10/20. In 2015 she developed acute painless loss, mainly peripheral in both eyes and central in the right: right 1/20, left 18/20. VEPs were strongly abnormal; ERGs and retina were normal. (charif2021dominantmutationsin pages 4-6)
Patient 2: Egyptian-born woman, age 47, without youthful visual complaints. One month after an uneventful cesarean delivery in 2002, painless loss began in the right eye (3/20), then left (10/20). Acuity progressed to 2/20 and 8/20 in 2012, and hand-motion and 4/20 in 2015. OCT showed bilateral RNFL collapse; IOP was 9/10 mmHg, VEPs were severely affected, and MRI was normal. (charif2021dominantmutationsin pages 4-6)
No EQ-5D, SF-36, PROMIS or disease-specific quality-of-life instrument was reported. Nevertheless, hand-motion vision in one eye, marked field constriction and bilateral acuity loss imply substantial limitations in mobility, driving, reading and occupational independence. Those functional consequences are clinically plausible but were not quantitatively assessed.
Gene: MIEF1; transcript used in the report NM_019008.5; protein MID51. The retrieved evidence does not provide a verified HGNC numeric identifier, so it is not inferred here. (charif2021dominantmutationsin pages 3-4)
Variant class: both are germline heterozygous missense substitutions. No frameshift, nonsense, splice, structural, somatic or chromosomal cause of OPA14 has been demonstrated. SNP-array testing in both patients found no chromosomal abnormality, copy-number variant or large homozygous interval. (charif2021dominantmutationsin pages 4-6)
Functional consequence: the data support an altered-function mechanism rather than simple mistargeting or failure to oligomerize. Both proteins reached mitochondria and formed monomers, dimers, tetramers and rare high-molecular-weight species similarly to wild type, but failed to produce the wild-type increase in mitochondrial fusion and disrupted network dynamics. p.Y240N directly affects the DRP1-interacting loop at residues 238–242. Whether the human disease mechanism is dominant-negative, partial loss of regulatory function, or another gain-of-abnormal-function effect remains unproven. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)
No modifier-gene, methylation, histone, chromatin, repeat-expansion or disease-specific epigenetic evidence is available.
No environmental toxin, ionizing radiation, pollution, occupational exposure, lifestyle behavior or infectious agent has been causally implicated. Lyme and Treponema serology were normal in Patient 1; anti-NMO and anti-MOG tests were negative in Patient 2. These findings helped exclude acquired inflammatory/infectious mimics rather than identify causal exposures. (charif2021dominantmutationsin pages 4-6)
MID51 is an integral outer-mitochondrial-membrane DRP1 adaptor. Its N-terminal transmembrane region anchors it, while a cytosolic nucleotidyltransferase-like domain binds ADP. General mechanistic studies indicate that ADP-bound MID51 stimulates DRP1 GTPase activity and oligomerization, connecting metabolic state to fission. Expression context matters: endogenous MID51 can organize productive DRP1 fission complexes, whereas overexpression can sequester inactive DRP1 and produce apparent mitochondrial elongation/fusion. This context dependence cautions against reducing OPA14 to simply “too much” or “too little” fission. (atkins2016theroleof pages 1-2, atkins2016theroleof pages 8-9, simpson2023posttranslationalcontrolof pages 52-57)
Suggested ontology annotations include:
There is no direct OPA14 evidence for immune-mediated pathology, respiratory-chain enzyme deficiency, altered metabolites/lipids, apoptosis measurements, mitophagy flux, mtDNA instability, transcriptomic signatures or RGC-specific bioenergetics. Those remain plausible downstream research areas rather than established annotations.
No disease-specific RNA-seq, single-cell sequencing, spatial transcriptomics, proteomics, metabolomics, lipidomics, methylomics, CRISPR screen, patient-derived iPSC, retinal organoid or multi-omics study was identified. The only functional system was transient expression of tagged wild-type or mutant MID51 in HeLa cells, assessed by confocal microscopy, immunoprecipitation and mito-PAGFP fusion assays. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)
Suggested anatomy terms: UBERON:0000966 retina, UBERON:0001785 retinal nerve fiber layer, UBERON:0000962 optic nerve, and mitochondrial outer membrane as the relevant GO cellular compartment. Exact identifiers should be release-validated before database import.
OPA14 appears to be a chronic, lifelong, progressive disorder with late-adult clinical recognition. A latent peripheral-field defect may precede perceived acuity loss by years. The reported course combines insidious early dysfunction with sudden painless subjective worsening, followed by continued progression over 10–13 years. Patient 1 preserved good left-eye acuity despite severe right-eye disease; Patient 2 progressed bilaterally to profound impairment. No remission, episodic recovery or treatment-induced improvement was documented. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
No formal staging system or progression-rate model exists. A practical observational scheme would be: early peripheral-field constriction; intermediate bilateral field/acuity involvement with disc pallor; advanced severe RNFL loss and profound visual impairment. This is a proposed clinical abstraction, not a validated scale.
Inheritance is classified as autosomal dominant/monoallelic, but the evidence is based on heterozygosity and functional studies rather than reported multigenerational segregation. Penetrance, age dependence, expressivity across families, de novo rate, parental mosaicism, anticipation and reproductive fitness are unknown. (OpenTargets Search: optic atrophy 14-MIEF1)
The original study found MIEF1 variants in 2/200 (1.0%) French molecularly unresolved inherited-optic-neuropathy referrals. This is a selected-cohort diagnostic fraction, not prevalence. (charif2021dominantmutationsin pages 3-4)
A 2023 analysis of 2,186 hereditary-optic-neuropathy probands reported an overall molecular diagnosis in 30%; the autosomal subgroup had 451 diagnoses among 1,680 referrals, and ten major genes accounted for 96% of those diagnoses. MIEF1 appeared in only two individuals among the rare-gene findings, confirming that it is a minor diagnostic contributor. Reported “1.08%” refers to the relevant diagnosed subgroup, not the general population. (rocatcher2023thetop10 pages 2-3, rocatcher2023thetop10 pages 1-1)
Population prevalence, annual incidence, geographic distribution, ancestry-specific enrichment and sex ratio cannot be estimated. Both known patients were women—one of Maghreb origin and one born in Egypt—but n=2 cannot support a female predisposition or North African founder effect.
The phenotype should prompt neuro-ophthalmic assessment comprising best-corrected acuity, color vision, pupils, slit-lamp examination, IOP, dilated funduscopy, automated and/or kinetic perimetry, optic-disc/RNFL and macular OCT, and VEP. ERG is useful when retinal dystrophy is a concern. Color-vision data were not reported in the defining cases. MRI of brain/orbits with contrast and inflammatory/infectious testing should be guided by presentation, particularly for acute or asymmetric loss.
Findings supporting OPA14 are bilateral pale/excavated discs with normal IOP, marked peripheral or superior-altitudinal field loss, progressive RNFL thinning and severely abnormal VEP despite an otherwise normal retina. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
The original 22-gene panel achieved >100× coverage for 95% of targeted bases, with Sanger fill-in of poorly covered regions. Modern broader panels or exome/genome sequencing are preferable because the 2023 cohort demonstrated extensive locus heterogeneity. (charif2021dominantmutationsin pages 4-6, rocatcher2023thetop10 pages 1-1)
Important alternatives include OPA1-dominant optic atrophy, LHON, WFS1/ACO2/MFN2/SPG7/AFG3L2-related neuropathies, glaucoma, toxic/nutritional optic neuropathy, compressive lesions, ischemic optic neuropathy, neuromyelitis-optica-spectrum disorder, MOG-associated disease and infectious optic neuropathy. Peripheral-to-central field progression, normal IOP, absent disc edema and a pathogenic functional MIEF1 variant favor OPA14, but no consensus diagnostic criteria exist. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
There is no newborn or population screening. Once a credible pathogenic familial variant is established, targeted cascade testing with pre-test counseling and baseline/serial ophthalmic assessment is appropriate. Testing asymptomatic minors requires individualized consideration because onset appears adult and no preventive therapy is proven.
The documented outcome is progressive, irreversible visual morbidity. Over approximately 13 years, Patient 2 reached hand-motion vision in the right eye and 4/20 in the left; Patient 1 reached 1/20 in the right while retaining 18/20 in the left. Thus, severe bilateral disability is possible, but asymmetry and retained useful vision can occur. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
No survival, mortality, life-expectancy, recovery-rate or validated prognostic-biomarker data exist. Neither patient had a life-limiting neurological syndrome, so available evidence supports vision-dominant morbidity rather than reduced survival. Prognostic inference from variant, onset age, OCT thickness or initial visual field is currently impossible.
No pharmacological, surgical, gene, cell, RNA or immune therapy is approved or clinically validated specifically for OPA14. No MIEF1-specific interventional trial or treatment-response series was identified. The 2021 report describes clinical progression, not a therapeutic intervention. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 4-6)
Current real-world management is therefore supportive:
Suggested NCIT-level intervention concepts include Genetic Counseling, Genetic Testing, Ophthalmologic Examination, Optical Coherence Tomography, Visual Field Test, Low Vision Rehabilitation, and Assistive Device; identifiers should be checked against the target NCIT release.
Recent 2023–2024 reviews discuss idebenone, coenzyme Q10, cysteamine/NAD⁺ strategies, AAV gene therapy, CRISPR and RNA therapies for other optic neuropathies. Idebenone is approved in Europe for LHON—not MIEF1 disease—and none should be prescribed as OPA14-directed therapy without evidence or a protocol. Experts emphasize integrating genotype and phenotype while recognizing that mitochondrial-dynamics therapeutics remain investigational. (d’esposito2024insightsonthe pages 11-12, d’esposito2024insightsonthe pages 1-2, d’esposito2024insightsonthe pages 12-14)
Primary prevention by lifestyle change, immunization or prophylactic medication is unavailable because OPA14 is genetic. Reproductive options after identification of a well-supported familial variant include genetic counseling, prenatal diagnosis and preimplantation genetic testing; these require discussion of uncertain penetrance and the limited variant evidence.
Secondary prevention consists of cascade testing and surveillance to detect presymptomatic field/RNFL changes, although no study proves that early detection alters progression. Tertiary prevention centers on low-vision care, fall-risk reduction, workplace adaptation and avoiding additional acquired optic-nerve injury. Vaccination and infectious-disease public-health measures have no disease-specific role.
No naturally occurring MIEF1-related optic atrophy was identified in companion animals, livestock or wildlife, and there is no zoonotic or cross-species transmission. MIEF1/MID51 biology is evolutionarily conserved among vertebrates, but conservation alone is not evidence of a homologous veterinary disorder. NCBI Taxon identifiers relevant to future comparative work include Homo sapiens: 9606 and Mus musculus: 10090; ortholog gene IDs should be verified directly in the current NCBI Gene release before import.
The disease-defining model was transfected HeLa cells, not an organismal or retinal model. Tagged p.Y240N and p.R146W proteins were tested for mitochondrial localization, oligomerization and fusion/network behavior by live-cell confocal microscopy and mito-PAGFP. This model provides strong evidence for variant-dependent organelle dysfunction but cannot reproduce RGC identity, optic-nerve architecture, age-dependent penetrance, visual-field loss or long-term neurodegeneration. (charif2021dominantmutationsin pages 3-4, charif2021dominantmutationsin pages 6-8)
No OPA14-specific knock-in/knockout mouse, rat, zebrafish, Drosophila, C. elegans, yeast, patient fibroblast, iPSC-RGC or retinal organoid model was identified. Priority models are heterozygous p.Y240N and p.R146W knock-in animals and patient-derived iPSC-RGCs, with endpoints including DRP1 recruitment, mitochondrial transport/fission/fusion, mitophagy, ATP/ROS, axonal survival, RNFL thickness and visual function.
The principal post-discovery development is diagnostic rather than therapeutic. The 2023, 2,186-proband study showed that comprehensive sequencing produces a 30% overall diagnostic rate, while MIEF1 remains among the individually rare contributors; this supports retaining MIEF1 on broad optic-neuropathy panels rather than using it as first-line single-gene testing. (rocatcher2023thetop10 pages 2-3, rocatcher2023thetop10 pages 1-1)
A 2024 review reinforced high energetic demand, mitochondrial dysfunction and oxidative stress as central to RGC vulnerability and highlighted genotype–phenotype integration and emerging molecular therapies. None of those advances has yet produced an OPA14-specific intervention. (d’esposito2024insightsonthe pages 11-12, d’esposito2024insightsonthe pages 1-2, d’esposito2024insightsonthe pages 2-4)
High confidence: MIEF1 association; the two reported variants and patient phenotypes; bilateral late-onset peripheral-field-predominant optic neuropathy; abnormal MID51 network regulation in HeLa-cell assays.
Moderate confidence: autosomal-dominant mechanism and nonsyndromic classification, because familial segregation and broader natural history remain unavailable.
Low or insufficient evidence: penetrance, population epidemiology, sex/ancestry effects, variant-specific prognosis, environmental triggers, protective factors, biochemical biomarkers, treatment, prevention of progression, advanced omics and organismal models.
The disease-defining abstract states: “Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields.” It further reports that the variants “do not disrupt MID51’s localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics.” (charif2021dominantmutationsin pages 1-3)
References
(OpenTargets Search: optic atrophy 14-MIEF1): Open Targets Query (optic atrophy 14-MIEF1, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(charif2021dominantmutationsin pages 1-3): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.
(charif2021dominantmutationsin pages 4-6): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.
(charif2021dominantmutationsin pages 3-4): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.
(charif2021dominantmutationsin pages 6-8): Majida Charif, Yvette C. Wong, Soojin Kim, Agnès Guichet, Catherine Vignal, Xavier Zanlonghi, Philippe Bensaid, Vincent Procaccio, Dominique Bonneau, Patrizia Amati-Bonneau, Pascal Reynier, Dimitri Krainc, and Guy Lenaers. Dominant mutations in mief1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy. Molecular Neurodegeneration, Feb 2021. URL: https://doi.org/10.1186/s13024-021-00431-w, doi:10.1186/s13024-021-00431-w. This article has 20 citations and is from a highest quality peer-reviewed journal.
(atkins2016theroleof pages 1-2): Kathleen Atkins, Asish Dasgupta, Kuang-Hueih Chen, Jeff Mewburn, and Stephen L. Archer. The role of drp1 adaptor proteins mid49 and mid51 in mitochondrial fission: implications for human disease. Clinical science, 130 21:1861-74, Nov 2016. URL: https://doi.org/10.1042/cs20160030, doi:10.1042/cs20160030. This article has 142 citations and is from a peer-reviewed journal.
(atkins2016theroleof pages 8-9): Kathleen Atkins, Asish Dasgupta, Kuang-Hueih Chen, Jeff Mewburn, and Stephen L. Archer. The role of drp1 adaptor proteins mid49 and mid51 in mitochondrial fission: implications for human disease. Clinical science, 130 21:1861-74, Nov 2016. URL: https://doi.org/10.1042/cs20160030, doi:10.1042/cs20160030. This article has 142 citations and is from a peer-reviewed journal.
(rocatcher2023thetop10 pages 2-3): Aude Rocatcher, Valérie Desquiret-Dumas, Majida Charif, Marc Ferré, Philippe Gohier, Delphine Mirebeau-Prunier, Christophe Verny, Dan Milea, Guy Lenaers, Catherine Vignal, Cédric Lamirel, Rabih Hage, Hélène Dollfus, Isabelle Meunier, Xavier Zanlonghi, Valérie Touitou, Pierre Lebranchu, Sylvie Odent, Caroline Froment Tilikete, Luc Jeanjean, Sabine Defoort-Dhellemmes, Isabelle Drumare-Bouvet, Vasily Smirnov, Catherine Vincent-Delorme, Damien Biotti, Fanny Varenne, Patrick Calvas, Nicolas Chassaing, Mickael Cohen, Christophe Orssaud, Fanny Mochel, Agathe Roubertie, Annick Toutain, Frédéric Pollet-Villard, Marie Noelle Bonnet Dupeyron, Céline Boulicot, Béatrice Cochener, Alice Goldenberg, Marie Line Jacquemont, Christine Francannet, Dominique Bonneau, Pascal Reynier, and Patrizia Amati-Bonneau. The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands. Brain : a journal of neurology, 146:455-460, Nov 2023. URL: https://doi.org/10.1093/brain/awac395, doi:10.1093/brain/awac395. This article has 53 citations.
(rocatcher2023thetop10 pages 1-1): Aude Rocatcher, Valérie Desquiret-Dumas, Majida Charif, Marc Ferré, Philippe Gohier, Delphine Mirebeau-Prunier, Christophe Verny, Dan Milea, Guy Lenaers, Catherine Vignal, Cédric Lamirel, Rabih Hage, Hélène Dollfus, Isabelle Meunier, Xavier Zanlonghi, Valérie Touitou, Pierre Lebranchu, Sylvie Odent, Caroline Froment Tilikete, Luc Jeanjean, Sabine Defoort-Dhellemmes, Isabelle Drumare-Bouvet, Vasily Smirnov, Catherine Vincent-Delorme, Damien Biotti, Fanny Varenne, Patrick Calvas, Nicolas Chassaing, Mickael Cohen, Christophe Orssaud, Fanny Mochel, Agathe Roubertie, Annick Toutain, Frédéric Pollet-Villard, Marie Noelle Bonnet Dupeyron, Céline Boulicot, Béatrice Cochener, Alice Goldenberg, Marie Line Jacquemont, Christine Francannet, Dominique Bonneau, Pascal Reynier, and Patrizia Amati-Bonneau. The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands. Brain : a journal of neurology, 146:455-460, Nov 2023. URL: https://doi.org/10.1093/brain/awac395, doi:10.1093/brain/awac395. This article has 53 citations.
(d’esposito2024insightsonthe pages 11-12): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.
(d’esposito2024insightsonthe pages 1-2): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.
(d’esposito2024insightsonthe pages 12-14): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.
(d’esposito2024insightsonthe pages 2-4): Fabiana D’Esposito, Marco Zeppieri, Maria Francesca Cordeiro, Matteo Capobianco, Alessandro Avitabile, Giuseppe Gagliano, Mutali Musa, Piero Barboni, and Caterina Gagliano. Insights on the genetic and phenotypic complexities of optic neuropathies. Genes, 15(12):1559, Nov 2024. URL: https://doi.org/10.3390/genes15121559, doi:10.3390/genes15121559. This article has 12 citations.
(simpson2023posttranslationalcontrolof pages 52-57): Post-translational control of mitochondria by Fbxo7 in Parkinson's disease This article has 0 citations.
Checked with linkml-reference-validator 0.2.1.
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| References checked | 5 |
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| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 5 |
| On topic | 5 |
| Off topic | 0 |
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| Outcome | Count |
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| Terms checked | 13 |
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| Unresolved (possible confabulation) | 0 |
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| Terms whose name was checked | 2 |
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| Terms named as a different term | 1 |
| Terms whose name is worth a second look | 1 |
These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0957824 (3 mentions) - the report calls it "if available"; MONDO calls it optic atrophy 14The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:
CL:0000740 (1 mention) - the report calls it "Cell Ontology: retinal ganglion cell"; CL calls it retinal ganglion cell