Methionine adenosyltransferase deficiency

Summary

Methionine adenosyltransferase deficiency (MONDO:0009607) is a disease caused by MAT1A (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include phosphatidylcholine.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MAT1A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 364
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	methionine adenosyltransferase deficiency
Mondo ID	MONDO:0009607
OMIM	250850
Orphanet	168598
NCIT	C123435
UMLS	C0268621
MedGen	75700
GARD	0008397
Is cancer (heuristic)	no

Also known as: brain demyelination due to methionine adenosyltransferase deficiency · hypermethioninemia, persistent, autosomal dominant, due to methionine adenosyltransferase I/III deficiency · isolated persistent hypermethioninemia · MAT deficiency · MAT I/III deficiency · methionine adenosyltransferase deficiency · methionine adenosyltransferase deficiency, autosomal recessive

Data availability: 364 ClinVar variants · 11 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › 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 methionine cycle and sulfur amino acid metabolism › methionine adenosyltransferase deficiency

Related subtypes (5): disorder of methionine catabolism, homocystinuria, cystathioninuria, encephalopathy due to sulfite oxidase deficiency, extraoral halitosis due to methanethiol oxidase deficiency

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

364 retrieved; paginated sample, class counts are floors:

188 uncertain significance, 87 likely benign, 25 conflicting classifications of pathogenicity, 25 pathogenic, 24 benign, 7 likely pathogenic, 6 pathogenic/likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3244818	NC_000010.10:g.(?81697608)(82049179_?)del	ANXA11	Pathogenic	criteria provided, single submitter
1202	NM_000429.3(MAT1A):c.966T>G (p.Ile322Met)	MAT1A	Pathogenic	criteria provided, single submitter
1204	NM_000429.3(MAT1A):c.1070C>T (p.Pro357Leu)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1205	NM_000429.3(MAT1A):c.914T>C (p.Leu305Pro)	MAT1A	Pathogenic	no assertion criteria provided
1206	NM_000429.3(MAT1A):c.826dup (p.Ala276fs)	MAT1A	Pathogenic	no assertion criteria provided
1207	NM_000429.3(MAT1A):c.1043_1044del (p.Val348fs)	MAT1A	Pathogenic	no assertion criteria provided
1208	NM_000429.3(MAT1A):c.791G>A (p.Arg264His)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1210	NM_000429.3(MAT1A):c.790C>T (p.Arg264Cys)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1452509	NM_000429.3(MAT1A):c.595C>T (p.Arg199Cys)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1969591	NM_000429.3(MAT1A):c.1042del (p.Val348fs)	MAT1A	Pathogenic	criteria provided, single submitter
2005287	NM_000429.3(MAT1A):c.705C>A (p.Tyr235Ter)	MAT1A	Pathogenic	criteria provided, single submitter
2082436	NM_000429.3(MAT1A):c.110T>C (p.Ile37Thr)	MAT1A	Pathogenic	criteria provided, single submitter
2103029	NM_000429.3(MAT1A):c.125_131del (p.Leu42fs)	MAT1A	Pathogenic	criteria provided, single submitter
2735423	NM_000429.3(MAT1A):c.964A>G (p.Ile322Val)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2735425	NM_000429.3(MAT1A):c.874C>T (p.Arg292Cys)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2742248	NC_000010.11:g.80275200del	MAT1A	Pathogenic	criteria provided, single submitter
279845	NM_000429.3(MAT1A):c.776C>T (p.Ala259Val)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
2836833	NM_000429.3(MAT1A):c.355C>T (p.Gln119Ter)	MAT1A	Pathogenic	criteria provided, single submitter
2839010	NM_000429.3(MAT1A):c.260T>A (p.Ile87Asn)	MAT1A	Pathogenic	criteria provided, single submitter
2841978	NM_000429.3(MAT1A):c.768+2T>A	MAT1A	Pathogenic	criteria provided, single submitter
285974	NM_000429.3(MAT1A):c.596G>A (p.Arg199His)	MAT1A	Pathogenic	criteria provided, multiple submitters, no conflicts
3375460	NM_000429.3(MAT1A):c.188G>T (p.Gly63Val)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3656125	NM_000429.3(MAT1A):c.456del (p.Thr153fs)	MAT1A	Pathogenic	criteria provided, single submitter
3692299	NM_000429.3(MAT1A):c.875G>T (p.Arg292Leu)	MAT1A	Pathogenic	criteria provided, single submitter
378112	NM_000429.3(MAT1A):c.763C>T (p.Pro255Ser)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
418870	NM_000429.3(MAT1A):c.895C>T (p.Arg299Cys)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4767583	NM_000429.3(MAT1A):c.821G>A (p.Trp274Ter)	MAT1A	Pathogenic	criteria provided, single submitter
578314	NM_000429.3(MAT1A):c.773A>T (p.Asp258Val)	MAT1A	Pathogenic	criteria provided, single submitter
647990	NM_000429.3(MAT1A):c.772G>T (p.Asp258Tyr)	MAT1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834512	NM_000429.3(MAT1A):c.1066C>T (p.Arg356Trp)	MAT1A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 2 · 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
MAT1A	Definitive	Autosomal recessive	methionine adenosyltransferase deficiency	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAT1A	Orphanet:168598	Methionine adenosyltransferase I/III deficiency
ANXA11	Orphanet:803	Amyotrophic lateral sclerosis

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
MAT1A	HGNC:6903	ENSG00000151224	Q00266	S-adenosylmethionine synthase isoform type-1	gencc,clinvar
ANXA11	HGNC:535	ENSG00000122359	P50995	Annexin A11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAT1A	S-adenosylmethionine synthase isoform type-1	Catalyzes the formation of S-adenosylmethionine from methionine and ATP.
ANXA11	Annexin A11	Binds specifically to calcyclin in a calcium-dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MAT1A	Enzyme (other)	yes	2.5.1.6	S-AdoMet_synthetase, S-AdoMet_synt_N, S-AdoMet_synt_central
ANXA11	Other/Unknown	no		Annexin, ANX11, Annexin_repeat_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
corpus epididymis	1
liver	1
right lobe of liver	1
lower esophagus mucosa	1
mucosa of transverse colon	1
palpebral conjunctiva	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAT1A	146	tissue_specific	marker	right lobe of liver, liver, corpus epididymis
ANXA11	300	ubiquitous	marker	lower esophagus mucosa, palpebral conjunctiva, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAT1A	3,118
ANXA11	1,344

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MAT1A	Q00266	4
ANXA11	P50995	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MAT1A causes MATD	1	11420.0×	0.001	MAT1A
Metabolism of ingested SeMet, Sec, MeSec into H2Se	1	1427.5×	0.004	MAT1A
Metabolic disorders of biological oxidation enzymes	1	878.5×	0.004	MAT1A
Methylation	1	815.7×	0.004	MAT1A
Sulfur amino acid metabolism	1	571.0×	0.004	MAT1A
Phase II - Conjugation of compounds	1	278.5×	0.007	MAT1A
Selenoamino acid metabolism	1	196.9×	0.009	MAT1A
Biological oxidations	1	129.8×	0.012	MAT1A
Diseases of metabolism	1	80.4×	0.017	MAT1A
Metabolism of amino acids and derivatives	1	67.6×	0.018	MAT1A
Disease	1	13.1×	0.083	MAT1A
Metabolism	1	11.6×	0.086	MAT1A

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
L-methionine catabolic process	1	8426.0×	8e-04	MAT1A
cytokinetic process	1	2808.7×	0.001	ANXA11
S-adenosylmethionine biosynthetic process	1	2106.5×	0.001	MAT1A
one-carbon metabolic process	1	561.7×	0.003	MAT1A
response to calcium ion	1	159.0×	0.008	ANXA11
phagocytosis	1	120.4×	0.008	ANXA11
protein homotetramerization	1	118.7×	0.008	MAT1A

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAT1A	0	0
ANXA11	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ANXA11	7	Binding:7
MAT1A	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MAT1A	2.5.1.6	methionine adenosyltransferase

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MAT1A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANXA11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MAT1A	4	—
ANXA11	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00006061	Not specified	COMPLETED	Study of Phosphatidylcholine in a Patient With Methionine Adenosyltransferase Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PHOSPHATIDYLCHOLINE	3	1