Mitochondrial dna depletion syndrome 21

Summary

Mitochondrial dna depletion syndrome 21 (MONDO:0976132) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial dna depletion syndrome 21
Mondo ID	MONDO:0976132
OMIM	621071
DOID	DOID:0051029
UMLS	C5975599
MedGen	1875129
GARD	0027427
Is cancer (heuristic)	no

Data availability: 5 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial DNA depletion syndrome › mitochondrial dna depletion syndrome 21

Related subtypes (20): Sengers syndrome, mitochondrial DNA depletion syndrome 1, mitochondrial DNA depletion syndrome, myopathic form, mitochondrial DNA depletion syndrome 4b, mitochondrial DNA depletion syndrome 11, mitochondrial DNA deletion syndrome with progressive myopathy, mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive, mitochondrial DNA depletion syndrome 14B (cardioencephalomyopathic type), mitochondrial DNA depletion syndrome 15 (hepatocerebral type), mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant, mitochondrial DNA depletion syndrome, encephalomyopathic form, mitochondrial dna depletion syndrome 16B (neuroophthalmic type), mitochondrial DNA depletion syndrome 20 (mngie type), mitochondrial DNA depletion syndrome 16 (hepatic type), mitochondrial DNA depletion syndrome 17, mitochondrial DNA depletion syndrome 18, mitochondrial DNA depletion syndrome 19, mitochondrial DNA depletion syndrome, hepatocerebral form, AFG3L2-related optic atrophy and/or spastic ataxia spectrum, mitochondrial dna depletion syndrome 14A (encephalomyopathic type)

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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3600308	GUK1, 25-BP INS, NT66_67	GUK1	Pathogenic	no assertion criteria provided
3600309	NM_001159390.2(GUK1):c.94G>A (p.Gly32Arg)	GUK1	Pathogenic	no assertion criteria provided
3600311	NM_001159390.2(GUK1):c.139C>T (p.Gln47Ter)	GUK1	Pathogenic	no assertion criteria provided
3600312	NM_001159390.2(GUK1):c.2T>G (p.Met1Arg)	GUK1	Pathogenic	no assertion criteria provided
3600310	NM_001159390.2(GUK1):c.61+1G>T	GUK1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GUK1	HGNC:4693	ENSG00000143774	Q16774	Guanylate kinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GUK1	Guanylate kinase	Catalyzes the phosphorylation of GMP to GDP.

Protein-family classification

Druggable: 1 · 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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GUK1	Kinase	yes	2.7.4.8	Guanylate_kin-like_dom, GK/Ca_channel_bsu, Guanylate_kinase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
amygdala	1
prefrontal cortex	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GUK1	300	ubiquitous	marker	right frontal lobe, prefrontal cortex, amygdala

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GUK1	3,686

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GUK1	Q16774	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 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
Azathioprine ADME	1	496.5×	0.005	GUK1
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.005	GUK1
Metabolism of nucleotides	1	300.5×	0.005	GUK1
Drug ADME	1	228.4×	0.005	GUK1
Metabolism	1	11.6×	0.086	GUK1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dGDP biosynthetic process	1	16852.0×	2e-04	GUK1
dATP metabolic process	1	16852.0×	2e-04	GUK1
GDP biosynthetic process	1	16852.0×	2e-04	GUK1
purine nucleotide metabolic process	1	5617.3×	3e-04	GUK1
glycoprotein transport	1	5617.3×	3e-04	GUK1
dGMP metabolic process	1	5617.3×	3e-04	GUK1
GDP-mannose metabolic process	1	2808.7×	5e-04	GUK1
nucleobase-containing small molecule interconversion	1	1685.2×	7e-04	GUK1
xenobiotic metabolic process	1	149.1×	0.007	GUK1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
GUK1	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
GUK1	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUK1	2.7.4.8	guanylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	GUK1
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)
GUK1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.