Autosomal recessive osteopetrosis 6

Summary

Autosomal recessive osteopetrosis 6 (MONDO:0012679) is a disease caused by PLEKHM1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: PLEKHM1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 23

Clinical features

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0004348	Abnormality of bone mineral density	Very frequent (80-99%)
HP:0002659	Increased susceptibility to fractures	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0003418	Back pain	Frequent (30-79%)
HP:0004618	Sandwich appearance of vertebral bodies	Frequent (30-79%)
HP:0004975	Erlenmeyer flask deformity of the femurs	Frequent (30-79%)
HP:0005652	Cortical sclerosis	Frequent (30-79%)
HP:0005746	Osteosclerosis of the base of the skull	Frequent (30-79%)
HP:0005789	Generalized osteosclerosis	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0003155	Elevated circulating alkaline phosphatase concentration	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Excluded (0%)
HP:0002901	Hypocalcemia	Excluded (0%)
HP:0000164	Abnormality of the dentition	Very rare (<1-4%)
HP:0000505	Visual impairment	Very rare (<1-4%)
HP:0000689	Dental malocclusion	Very rare (<1-4%)
HP:0001293	Cranial nerve compression	Very rare (<1-4%)
HP:0001433	Hepatosplenomegaly	Very rare (<1-4%)
HP:0002754	Osteomyelitis	Very rare (<1-4%)
HP:0006482	Abnormal dental morphology	Very rare (<1-4%)
HP:0007958	Optic atrophy from cranial nerve compression	Very rare (<1-4%)
HP:0031035	Chronic infection	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 6
Mondo ID	MONDO:0012679
MeSH	C566931
OMIM	611497
Orphanet	210110
DOID	DOID:0110945
UMLS	C1969093
MedGen	409754
GARD	0004156
Is cancer (heuristic)	no

Also known as: autosomal recessive intermediate osteopetrosis · autosomal recessive osteopetrosis type 6 · OPTB6 · osteopetrosis (disease) caused by mutation in PLEKHM1 · osteopetrosis autosomal recessive 6 · osteopetrosis autosomal recessive intermediate form · osteopetrosis, autosomal recessive 6 · osteopetrosis, autosomal recessive type 6 · PLEKHM1 osteopetrosis (disease)

Data availability: 3 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive osteopetrosis › autosomal recessive osteopetrosis 6

Related subtypes (9): autosomal recessive osteopetrosis 1, autosomal recessive osteopetrosis 2, autosomal recessive osteopetrosis 5, autosomal recessive osteopetrosis 3, autosomal recessive osteopetrosis 4, autosomal recessive osteopetrosis 7, leukocyte adhesion deficiency 3, autosomal recessive osteopetrosis 8, osteopetrosis, autosomal recessive 9

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

3 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
922	NM_014798.3(PLEKHM1):c.296+1G>A	PLEKHM1	Pathogenic	no assertion criteria provided
1174843	NM_014798.3(PLEKHM1):c.1348C>A (p.Pro450Thr)	PLEKHM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892118	NM_014798.3(PLEKHM1):c.1802A>G (p.Lys601Arg)	PLEKHM1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 8 · 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
CLCN7	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 4	16
TCIRG1	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 1	9
PLEKHM1	Strong	Autosomal recessive	autosomal recessive osteopetrosis 6	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEKHM1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
CLCN7	Orphanet:210110	Intermediate osteopetrosis
CLCN7	Orphanet:53	Albers-Schönberg osteopetrosis
CLCN7	Orphanet:667	Autosomal recessive malignant osteopetrosis

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEKHM1	HGNC:29017	ENSG00000225190	Q9Y4G2	Pleckstrin homology domain-containing family M member 1	gencc,clinvar
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	gencc
CLCN7	HGNC:2025	ENSG00000103249	P51798	H(+)/Cl(-) exchange transporter 7	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLEKHM1	Pleckstrin homology domain-containing family M member 1	Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways.
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
CLCN7	H(+)/Cl(-) exchange transporter 7	Slowly voltage-gated channel mediating the exchange of chloride ions against protons.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEKHM1	Scaffold/PPI	no		PH_domain, PKC_DAG/PE, Run_dom
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
CLCN7	Other/Unknown	no		CBS_dom, ClC, CIC-7

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	2
esophagus mucosa	1
lower esophagus mucosa	1
granulocyte	1
spleen	1
left adrenal gland cortex	1
metanephros cortex	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEKHM1	134	broad	yes	lower esophagus mucosa, esophagus mucosa, blood
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
CLCN7	296	ubiquitous	marker	metanephros cortex, right adrenal gland cortex, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN7	1,991
TCIRG1	1,931
PLEKHM1	1,038

Intra-cohort edges

A	B	Sources
CLCN7	PLEKHM1	string_interaction
CLCN7	TCIRG1	string_interaction
PLEKHM1	TCIRG1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN7	P51798	9
PLEKHM1	Q9Y4G2	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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
Insulin receptor recycling	1	190.3×	0.014	TCIRG1
Transferrin endocytosis and recycling	1	184.2×	0.014	TCIRG1
ROS and RNS production in phagocytes	1	167.9×	0.014	TCIRG1
Amino acids regulate mTORC1	1	100.2×	0.017	TCIRG1
Stimuli-sensing channels	1	68.0×	0.021	CLCN7
Ion channel transport	1	48.0×	0.024	TCIRG1
Neutrophil degranulation	1	11.5×	0.085	TCIRG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to silver ion	1	5617.3×	0.004	TCIRG1
dentin mineralization	1	5617.3×	0.004	TCIRG1
protein catabolic process in the vacuole	1	2808.7×	0.004	TCIRG1
memory T cell activation	1	2808.7×	0.004	TCIRG1
regulation of proton transport	1	1872.4×	0.004	TCIRG1
T-helper 1 cell activation	1	1872.4×	0.004	TCIRG1
osteoclast proliferation	1	1123.5×	0.005	TCIRG1
tooth eruption	1	1123.5×	0.005	TCIRG1
response to pH	1	936.2×	0.005	CLCN7
pH reduction	1	802.5×	0.005	TCIRG1
establishment of vesicle localization	1	802.5×	0.005	TCIRG1
phagosome acidification	1	802.5×	0.005	TCIRG1
transepithelial chloride transport	1	624.1×	0.006	CLCN7
ruffle organization	1	432.1×	0.007	TCIRG1
regulation of osteoblast differentiation	1	432.1×	0.007	TCIRG1
optic nerve development	1	401.2×	0.007	TCIRG1
autophagosome-lysosome fusion	1	401.2×	0.007	PLEKHM1
enamel mineralization	1	401.2×	0.007	TCIRG1
positive regulation of bone resorption	1	330.4×	0.007	PLEKHM1
positive regulation of ruffle assembly	1	330.4×	0.007	PLEKHM1
late endosome to lysosome transport	1	330.4×	0.007	PLEKHM1
vacuolar acidification	1	244.2×	0.009	TCIRG1
immunoglobulin mediated immune response	1	234.1×	0.009	TCIRG1
lysosomal lumen acidification	1	224.7×	0.009	TCIRG1
bone resorption	1	193.7×	0.010	TCIRG1
hematopoietic stem cell homeostasis	1	187.2×	0.010	TCIRG1
cellular response to cytokine stimulus	1	181.2×	0.010	TCIRG1
lysosome localization	1	175.5×	0.010	PLEKHM1
T cell homeostasis	1	151.8×	0.011	TCIRG1
regulation of insulin secretion	1	130.6×	0.012	TCIRG1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLEKHM1	0	0
TCIRG1	0	0
CLCN7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
E	Difficult family or no structure, no drug	3	PLEKHM1, TCIRG1, CLCN7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLEKHM1	0	—
TCIRG1	0	—
CLCN7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.