MTMR2

protein-coding

myotubularin related protein 2, the group of Myotubularins|Phosphoinositide phosphatases

Gene summary

This gene is a member of the myotubularin family of phosphoinositide lipid phosphatases. The encoded protein possesses phosphatase activity towards phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Mutations in this gene are a cause of Charcot-Marie-Tooth disease type 4B, an autosomal recessive demyelinating neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

Previous symbols:

CMT4B

MANE transcript

NM_016156.6

Inheritance

ClinVar variants

P:70U:243B:119

Top phenotype

Charcot-Marie-Tooth disease, type 4B1

gnomAD constraint

pLI —, LoF o/e 0.44

Max pathogenic AF

—

Genomic locus

chr11:95,821,766-95,925,315

External References & Databases

Ensembl (ENSG00000087053)

Transcript & Mutation Effects

hg38 • Region Span ~103.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 4B1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011066

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 4B1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011066

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 4B1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011066

Submitter: Orphanet

Charcot-Marie-Tooth disease type 4B1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011066

Submitter: PanelApp Australia

demyelinating hereditary motor and sensory neuropathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018776

Submitter: ClinGen

MTMR2 was first reported in relation to autosomal recessive demyelinating hereditary motor and sensory neuropathy, and more specifically Charcot Marie Tooth type 4B1 in 2000 (Bolino et al., 2000; PMID: 10802647). The phenotype associated with MTMR2 including vocal paresis, severe neuropathy at an early onset (adolescents), and pathologically with the presence of myelin outfolding (reviewed in Tazir et al., 2013; PMID: 23781959). At least 25 unique variants, including missense, nonsense, frameshift, and indels have been reported in humans (reviewed in Pareyson et al., 2019, PMID: 31070812 and per the Inherited Neuropathy Variant Database). There are variant databases describing MTMR2 variants of interest in neuropathy, including (1) the Inherited Neuropathy Variant Database (URL: http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/) and (2) the MTMR2 LOVD database (https://databases.lovd.nl/shared/genes/MTMR2). Evidence supporting this gene-disease relationship includes case-level data, segregation and experimental data. This gene-disease relationship has been well studied and the case-level data does not reflect all published studies. This gene-disease relationship is supported by expression studies, protein interaction, animal models and rescue models. MTMR2 has 18 exons, and produces several transcripts due to two start sites (exon 1 and exon 3). Studies have indicated that nonsense mutations may not result in loss of protein expression, as the truncated proteins remain expressed in patient cells (Prevatali et al., 2003 PMID:1335693). The molecular mechanism is predicted to be loss of phosphatase activity (reviewed in Raghu et al., 2019; PMID: 31507376; Tazir et al., 2013; PMID: 23781959). In summary, MTMR2 is DEFINITIVELY associated with autosomal recessive demyelinating hereditary motor and sensory neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Feb 11, 2020.

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, type 4B1AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 10802647

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MTMR2 variants in ClinVar

8 Conditions Cataloged

Charcot-Marie-Tooth disease type 4Total: 434

Inborn genetic diseasesTotal: 123

not providedTotal: 82

Charcot-Marie-Tooth disease type 4B1Total: 76

not specifiedTotal: 42

Charcot-Marie-Tooth diseaseTotal: 38

MTMR2-related disorderTotal: 36

MTMR2-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016156.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	106 clinvar	2 clinvar	112
missense		5 clinvar	217 clinvar	9 clinvar	2 clinvar	233
nonsense	15 clinvar	12 clinvar	1 clinvar			28
start loss						0
frameshift	14 clinvar	13 clinvar	9 clinvar			36
splice donor/acceptor (+/-2bp)	3 clinvar	8 clinvar	12 clinvar			23
Total	32	38	243	115	4	432

Highest pathogenic variant AF is 0.00013882795

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 107 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016156.6	RefSeq	NP_057240.3	15	MANE Select
ENST00000346299.10	Ensembl	ENSP00000345752.6	15	MANE Select
NM_001243571.2	RefSeq	NP_001230500.1	13	Standard
NM_001440630.1	RefSeq	NP_001427559.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)
Metabolism of lipids
Metabolism
Nicotinate Nicotinamide metabolism

Biological Process

negative regulation of receptor internalization
protein dephosphorylation
phosphatidylinositol biosynthetic process
negative regulation of myelination
myelin assembly

Molecular Function

phosphatidylinositol-3-phosphatase activity
protein tyrosine phosphatase activity
protein binding
protein tyrosine/serine/threonine phosphatase activity
protein homodimerization activity

Cellular Component

nucleus
cytoplasm
vacuolar membrane
cytosol
synaptic vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346299
Coding exons: 15
Length: 92434
Individuals with no LoFs: 125688
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125746
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.22	272	335	0.813	0.0000171	4175
Missense (PolyPhen)		45	86.054	0.52293		1108
Synonymous	2.02	91	119	0.764	0.00000576	1225
Loss of Function	3.31	18	40.8	0.441	0.00000274	438

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.00042	0.00042	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Phosphatase that acts on lipids with a phosphoinositol headgroup. Has phosphatase activity towards phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate. {ECO:0000269|PubMed:11733541, ECO:0000269|PubMed:12668758, ECO:0000269|PubMed:21372139}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 4B1 (CMT4B1) [MIM:601382]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. {ECO:0000269|PubMed:10802647, ECO:0000269|PubMed:12398840}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.218

Intolerance Scores

LoFtool: 0.101
RVIS EVS: 0.33
RVIS percentile EVS: 73.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.957

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium