3-methylglutaconic aciduria type 8

Summary

3-methylglutaconic aciduria type 8 (MONDO:0044723) is a disease caused by HTRA2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: HTRA2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	3-methylglutaconic aciduria type 8
Mondo ID	MONDO:0044723
OMIM	617248
Orphanet	505208
DOID	DOID:0070000
UMLS	C4310650
MedGen	934617
GARD	0022050
Is cancer (heuristic)	no

Also known as: 3-methylglutaconic aciduria, type VIII · 3-methylglutaconic aciduria, type VIII; MGCA8 · MGA8 · MGCA8

Data availability: 18 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › inborn organic aciduria › classic organic aciduria › 3-methylglutaconic aciduria › 3-methylglutaconic aciduria type 8

Related subtypes (9): 3-methylglutaconic aciduria type 1, 3-methylglutaconic aciduria type 4, 3-methylglutaconic aciduria type 3, Barth syndrome, 3-methylglutaconic aciduria type 5, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 3-methylglutaconic aciduria, type VIIB, 3-methylglutaconic aciduria type 9, 3-methylglutaconic aciduria, type VIIA

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

18 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 pathogenic, 3 likely pathogenic, 1 likely benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1455851	NM_013247.5(HTRA2):c.1138C>T (p.Arg380Ter)	HTRA2	Pathogenic	criteria provided, multiple submitters, no conflicts
372210	NM_013247.5(HTRA2):c.1316_1320del (p.Val439fs)	HTRA2	Pathogenic	no assertion criteria provided
372211	NM_013247.5(HTRA2):c.906+1G>C	HTRA2	Pathogenic	no assertion criteria provided
372212	NM_013247.5(HTRA2):c.728_730delinsCAT (p.Leu243_Pro244delinsProSer)	HTRA2	Pathogenic	no assertion criteria provided
1452957	NM_013247.5(HTRA2):c.573dup (p.Leu192fs)	LOC129934141	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372209	NM_013247.5(HTRA2):c.1211G>A (p.Arg404Gln)	LOXL3	Pathogenic	criteria provided, single submitter
1252041	NM_013247.5(HTRA2):c.1013_1015del (p.Leu338del)	HTRA2	Likely pathogenic	no assertion criteria provided
3384181	NM_013247.5(HTRA2):c.1216G>T (p.Gly406Cys)	HTRA2	Likely pathogenic	criteria provided, single submitter
3586941	NM_013247.5(HTRA2):c.420del (p.Ala141fs)	HTRA2	Likely pathogenic	criteria provided, single submitter
1027794	NM_013247.5(HTRA2):c.146G>C (p.Arg49Pro)	HTRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1385413	NM_013247.5(HTRA2):c.1294C>T (p.Arg432Ter)	HTRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2188914	NM_013247.5(HTRA2):c.755G>A (p.Arg252Gln)	HTRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3586942	NM_013247.5(HTRA2):c.508C>A (p.His170Asn)	HTRA2	Uncertain significance	criteria provided, single submitter
898769	NM_013247.5(HTRA2):c.77G>A (p.Gly26Glu)	HTRA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
973448	NM_013247.5(HTRA2):c.739C>T (p.Arg247Cys)	HTRA2	Uncertain significance	criteria provided, single submitter
1188327	NM_013247.5(HTRA2):c.618C>G (p.Val206=)	HTRA2	Likely benign	criteria provided, multiple submitters, no conflicts
337129	NM_013247.5(HTRA2):c.480C>G (p.Ala160=)	HTRA2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
4342	NM_013247.5(HTRA2):c.421G>T (p.Ala141Ser)	HTRA2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
HTRA2	Definitive	Autosomal recessive	3-methylglutaconic aciduria type 8	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HTRA2	Orphanet:2828	Young-onset Parkinson disease
HTRA2	Orphanet:505208	3-methylglutaconic aciduria type 8
LOXL3	Orphanet:250984	Autosomal recessive Stickler syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HTRA2	HGNC:14348	ENSG00000115317	O43464	Serine protease HTRA2, mitochondrial	gencc,clinvar
LOXL3	HGNC:13869	ENSG00000115318	P58215	Lysyl oxidase homolog 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HTRA2	Serine protease HTRA2, mitochondrial	Serine protease that shows proteolytic activity against a non-specific substrate beta-casein.
LOXL3	Lysyl oxidase homolog 3	Protein-lysine 6-oxidase that mediates the oxidation of peptidyl lysine residues to allysine in target proteins.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	18.3×	0.108
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HTRA2	Protease	yes	3.4.21.108	PDZ, Peptidase_S1C, Peptidase_S1_PA
LOXL3	Enzyme (other)	yes	1.4.3.13	SRCR, Lysyl_oxidase, Lysyl_oxidase_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
right coronary artery	1
trabecular bone tissue	1
cartilage tissue	1
tendon of biceps brachii	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HTRA2	280	ubiquitous	marker	cortical plate, right coronary artery, trabecular bone tissue
LOXL3	198	ubiquitous	marker	tibia, cartilage tissue, tendon of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HTRA2	4,023
LOXL3	1,130

Intra-cohort edges

A	B	Sources
HTRA2	LOXL3	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HTRA2	O43464	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LOXL3	P58215	84.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial unfolded protein response (UPRmt)	1	300.5×	0.010	HTRA2
Crosslinking of collagen fibrils	1	285.5×	0.010	LOXL3
Collagen formation	1	228.4×	0.010	LOXL3
Elastic fibre formation	1	167.9×	0.010	LOXL3
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.014	LOXL3
Mitochondrial protein degradation	1	57.1×	0.020	HTRA2
Extracellular matrix organization	1	31.6×	0.031	LOXL3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pentacyclic triterpenoid metabolic process	1	8426.0×	0.003	HTRA2
negative regulation of type 2 mitophagy	1	4213.0×	0.003	HTRA2
fibronectin fibril organization	1	4213.0×	0.003	LOXL3
peptidyl-lysine oxidation	1	2808.7×	0.004	LOXL3
response to herbicide	1	1685.2×	0.005	HTRA2
regulation of autophagy of mitochondrion	1	1404.3×	0.005	HTRA2
negative regulation of T-helper 17 cell lineage commitment	1	1203.7×	0.005	LOXL3
mitochondrial protein catabolic process	1	766.0×	0.006	HTRA2
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	766.0×	0.006	HTRA2
programmed cell death	1	648.1×	0.006	HTRA2
positive regulation of integrin-mediated signaling pathway	1	648.1×	0.006	LOXL3
somite development	1	561.7×	0.006	LOXL3
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	468.1×	0.007	HTRA2
positive regulation of execution phase of apoptosis	1	421.3×	0.007	HTRA2
ceramide metabolic process	1	401.2×	0.007	HTRA2
execution phase of apoptosis	1	383.0×	0.007	HTRA2
protein autoprocessing	1	324.1×	0.007	HTRA2
regulation of multicellular organism growth	1	324.1×	0.007	HTRA2
cellular response to interferon-beta	1	263.3×	0.008	HTRA2
spinal cord development	1	255.3×	0.008	LOXL3
adult walking behavior	1	247.8×	0.008	HTRA2
obsolete positive regulation of protein targeting to mitochondrion	1	247.8×	0.008	HTRA2
forebrain development	1	175.5×	0.010	HTRA2
cellular response to heat	1	172.0×	0.010	HTRA2
intrinsic apoptotic signaling pathway in response to DNA damage	1	162.0×	0.010	HTRA2
cellular response to growth factor stimulus	1	159.0×	0.010	HTRA2
epithelial to mesenchymal transition	1	156.0×	0.010	LOXL3
negative regulation of cell cycle	1	145.3×	0.011	HTRA2
neuron development	1	127.7×	0.011	HTRA2
roof of mouth development	1	123.9×	0.011	LOXL3

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LOXL3	PYRITHIONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LOXL3	3	4
HTRA2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
THIRAM	2	LOXL3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HTRA2	11	Binding:11
LOXL3	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HTRA2	3.4.21.108	HtrA2 peptidase
LOXL3	1.4.3.13	protein-lysine 6-oxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PYRITHIONE	4	LOXL3
DISULFIRAM	4	LOXL3
THIRAM	2	LOXL3

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LOXL3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HTRA2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HTRA2	11	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.