Hypermanganesemia with dystonia 2

Summary

Hypermanganesemia with dystonia 2 (MONDO:0014864) is a disease caused by SLC39A14 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC39A14 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 22
• Phenotypes (HPO): 26

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

26 HPO clinical features (Orphanet curated; top 26 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Frequent (30-79%)
HP:0000338	Hypomimic face	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002059	Cerebral atrophy	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002376	Developmental regression	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002483	Bulbar signs	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002828	Multiple joint contractures	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0008936	Axial hypotonia	Frequent (30-79%)
HP:0011448	Ankle clonus	Frequent (30-79%)
HP:0012048	Oromandibular dystonia	Frequent (30-79%)
HP:0012407	Scissor gait	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0032097	Hypermanganesemia	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypermanganesemia with dystonia 2
Mondo ID	MONDO:0014864
OMIM	617013
Orphanet	521406
DOID	DOID:0080537
SNOMED CT	768554008
UMLS	C4310765
MedGen	934732
GARD	0017958
Is cancer (heuristic)	no

Also known as: HMNDYT2 · hypermanganesemia with dystonia 2 · hypermanganesemia with dystonia 2; HMNDYT2 · hypermanganesemia with dystonia caused by mutation in SLC39A14 · hypermanganesemia with dystonia type 2 · SLC39A14 hypermanganesemia with dystonia

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › hypermanganesemia with dystonia › hypermanganesemia with dystonia 2

Related subtypes (1): cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome

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

22 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 benign, 4 likely pathogenic, 3 uncertain significance, 2 not provided, 1 benign/likely benign, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334419	NM_001128431.4(SLC39A14):c.1336C>T (p.Pro446Ser)	SLC39A14	Pathogenic	no assertion criteria provided
242924	NM_001128431.4(SLC39A14):c.292T>G (p.Phe98Val)	SLC39A14	Pathogenic	no assertion criteria provided
242925	NM_001128431.4(SLC39A14):c.313G>T (p.Glu105Ter)	SLC39A14	Pathogenic	no assertion criteria provided
242926	NM_015359.6(SLC39A14):c.477_478del (p.Ser160fs)	SLC39A14	Pathogenic	no assertion criteria provided
242927	NM_001128431.4(SLC39A14):c.1147G>A (p.Gly383Arg)	SLC39A14	Pathogenic	no assertion criteria provided
242928	NM_001128431.4(SLC39A14):c.1407C>G (p.Asn469Lys)	SLC39A14	Pathogenic	no assertion criteria provided
3775321	NM_015359.6(SLC39A14):c.520dup (p.Val174fs)	SLC39A14	Pathogenic	criteria provided, single submitter
2506025	NM_001128431.4(SLC39A14):c.628-2A>G	SLC39A14	Likely pathogenic	criteria provided, single submitter
4086055	NM_001128431.4(SLC39A14):c.152A>G (p.Tyr51Cys)	SLC39A14	Likely pathogenic	criteria provided, single submitter
446707	NM_001128431.4(SLC39A14):c.751-9C>G	SLC39A14	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4686585	NM_001128431.4(SLC39A14):c.971G>A (p.Trp324Ter)	SLC39A14	Likely pathogenic	criteria provided, single submitter
985470	NM_001128431.4(SLC39A14):c.382C>T (p.Arg128Trp)	SLC39A14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4278009	NM_002905.5(RDH5):c.487A>G (p.Ser163Gly)	BLOC1S1-RDH5	Uncertain significance	criteria provided, single submitter
3780945	NM_001128431.4(SLC39A14):c.-16+12107G>A	SLC39A14	Uncertain significance	criteria provided, single submitter
452630	NM_001128431.4(SLC39A14):c.1066G>A (p.Gly356Ser)	SLC39A14	Uncertain significance	criteria provided, single submitter
1230736	NM_001128431.4(SLC39A14):c.457+45G>T	SLC39A14	Benign	criteria provided, multiple submitters, no conflicts
1241953	NM_001128431.4(SLC39A14):c.195A>G (p.Leu65=)	SLC39A14	Benign	criteria provided, multiple submitters, no conflicts
1286124	NM_001128431.4(SLC39A14):c.98T>C (p.Leu33Pro)	SLC39A14	Benign	criteria provided, multiple submitters, no conflicts
1286943	NM_001128431.4(SLC39A14):c.1333-25G>A	SLC39A14	Benign	criteria provided, multiple submitters, no conflicts
1627844	NM_001128431.4(SLC39A14):c.939+8G>C	SLC39A14	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
446705	NM_001128431.4(SLC39A14):c.367C>T (p.Gln123Ter)	SLC39A14	not provided	no classification provided
446706	NM_015359.6(SLC39A14):c.512G>A (p.Gly171Glu)	SLC39A14	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
SLC39A14	Strong	Autosomal recessive	hypermanganesemia with dystonia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC39A14	Orphanet:521406	Dystonia-parkinsonism-hypermanganesemia syndrome

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
SLC39A14	HGNC:20858	ENSG00000104635	Q15043	Metal cation symporter ZIP14	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC39A14	Metal cation symporter ZIP14	Electroneutral transporter of the plasma membrane mediating the cellular uptake of the divalent metal cations zinc, manganese and iron that are important for tissue homeostasis, metabolism, development and immunity.

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
Transporter	1	77.8×	0.013

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC39A14	Transporter	yes		ZIP, ZIP_Transporter

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
body of pancreas	1
cartilage tissue	1
liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC39A14	288	ubiquitous	marker	cartilage tissue, body of pancreas, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC39A14	1,467

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC39A14	Q15043	73.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Zinc transporters	1	1142.0×	0.003	SLC39A14
Zinc influx into cells by the SLC39 gene family	1	1142.0×	0.003	SLC39A14
Metal ion SLC transporters	1	601.0×	0.003	SLC39A14
R-HSA-425366	1	181.3×	0.008	SLC39A14
SLC-mediated transmembrane transport	1	59.2×	0.020	SLC39A14
Transport of small molecules	1	25.1×	0.040	SLC39A14

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
manganese ion homeostasis	1	16852.0×	0.001	SLC39A14
iron import into cell	1	5617.3×	0.001	SLC39A14
manganese ion transmembrane transport	1	5617.3×	0.001	SLC39A14
import across plasma membrane	1	4213.0×	0.001	SLC39A14
regulation of hormone levels	1	3370.4×	0.001	SLC39A14
iron ion transmembrane transport	1	2407.4×	0.001	SLC39A14
zinc ion import across plasma membrane	1	1685.2×	0.001	SLC39A14
intracellular monoatomic cation homeostasis	1	1123.5×	0.002	SLC39A14
positive regulation of G protein-coupled receptor signaling pathway	1	1053.2×	0.002	SLC39A14
obsolete inorganic cation transmembrane transport	1	936.2×	0.002	SLC39A14
zinc ion transmembrane transport	1	702.2×	0.002	SLC39A14
intracellular zinc ion homeostasis	1	481.5×	0.003	SLC39A14
gluconeogenesis	1	324.1×	0.004	SLC39A14
chondrocyte differentiation	1	300.9×	0.004	SLC39A14
cellular response to glucose stimulus	1	267.5×	0.004	SLC39A14
insulin receptor signaling pathway	1	221.7×	0.005	SLC39A14
cellular response to insulin stimulus	1	170.2×	0.006	SLC39A14

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
SLC39A14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC39A14	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	1	SLC39A14
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)
SLC39A14	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.