MERTK

protein-coding

MER proto-oncogene, tyrosine kinase, the group of Receptor tyrosine kinases|Fibronectin type III domain containing|I-set domain containing

Gene summary

This gene is a member of the MER/AXL/TYRO3 receptor kinase family and encodes a transmembrane protein with two fibronectin type-III domains, two Ig-like C2-type (immunoglobulin-like) domains, and one tyrosine kinase domain. Mutations in this gene have been associated with disruption of the retinal pigment epithelium (RPE) phagocytosis pathway and onset of autosomal recessive retinitis pigmentosa (RP). [provided by RefSeq, Jul 2008]

MANE transcript

NM_006343.3

Inheritance

AR, AD

ClinVar variants

P:147U:442B:217

Top phenotype

Retinitis pigmentosa 38

gnomAD constraint

pLI —, LoF o/e 0.54

Max pathogenic AF

—

Genomic locus

chr2:111,898,607-112,029,561

External References & Databases

Ensembl (ENSG00000153208)

Transcript & Mutation Effects

hg38 • Region Span ~131.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 38STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013469

Submitter: PanelApp Australia

retinitis pigmentosa 38DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013469

Submitter: G2P

retinitis pigmentosa 38STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013469

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

MERTK-related retinopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800394

Submitter: ClinGen

The relationship between *MERTK* and an autosomal recessive inherited retinal dystrophy, MERTK-related retinopathy, was evaluated using the ClinGen Clinical Validity Framework as of July 7, 2022. The disease entity has previously been described as retinitis pigmentosa 38. To encompass a range of phenotypes and to account for the genetic heterogeneity in inherited retinopathy, the disease entity used for this curation is MERTK-related retinopathy (MONDO:0800394). *MERTK* (MER proto-oncogene, tyrosine kinase) (MIM*604705) is localized to chromosome 2q14.1 and consists of 19 exons (Weier, Fung, & Lersch, 1999). It encodes the tyrosine-protein kinase Mer, a 999-amino-acid transmembrane protein (Uniprot#Q12866) belonging to the TAM (TYRO3/AXL/MER) receptor kinase family. MERTK is highly expressed in monocyte/macrophages, and in epithelial cells including the Retina Pigment Epithelium (RPE). It plays a critical role in the shedding of photoreceptor outer segments prior to phagocytosis, a circadian process essential for photoreceptor homeostasis (Feng et al., 2002). *MERTK* was first associated with retinopathy after the identification of a deletion in the gene causing the naturally occurring autosomal recessive (AR) retinal degeneration of the Royal College of Surgeons (RCS) rat (D'Cruz et al., 2000), a retinal dystrophy model secondary to a phagocytic defect of the RPE. Biallelic variants in *MERTK* underlying retinopathy in humans were first reported by Gal et al. (2000). The associated retinopathy phenotype is usually severe, characterized by an early onset of the disease, with night blindness and progressive visual field constriction due to loss of rod photoreceptors, and rapid macular involvement. A total of 79 variants have already been identified underlying rod-cone dystrophy. The variant spectrum in *MERTK* includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, 2 small insertion–deletions, 3 small duplications, and 2 exonic and 3 gross deletions (PMID: 29659094). Altogether, variants in *MERTK* account for ∼2% of retinopathy cases with a severe phenotype. No specific phenotype/genotype correlations have been reported, most likely due to the diversity of the variant spectrum in a yet limited number of patients. In this curation, data from 3 consanguineous families with multiple patients and 3 isolated individuals with 8 unique variants (nonsense, frameshift, missense), were collected from 6 publications (Ksantini M, et al., 2012, PMID: 22180149, Bhatia S, et al., 2019, PMID: 30851773, McHenry CL, et al., 2004, PMID: 15111602, Lukovic D, et al., 2015, PMID: 26263531, Mackay DS, et al., 2010, PMID: 20300561, Biswas P, et al., 2021, PMID: 33252167). More data is available in the literature but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is supported by functional studies and model systems, described above (D'Cruz PM, et al., 2000, PMID: 10699188, Lukovic D, et al., 2015, PMID: 26263531, McHenry CL, et al., 2004, PMID: 15111602, Duncan JL, et al., 2003, PMID: 12556419). Results described by D'Cruz PM, et al., 2000, PMID: 10699188, provide genetic evidence for an essential role of a receptor tyrosine kinase in a specialized form of phagocytosis and suggest a molecular model for ingestion of outer segments by RPE cells. In summary, *ΜΕRΤΚ* is definitively associated with the autosomal recessive inherited retinal dystrophy, MERTK-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 7, 2022.

Clinical Genomic Database (CGD)

Retinitis pigmentosa 38AD/AR

Manifestation: Ophthalmologic

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: 11062461; 11727200; 17301963; 22180149

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MERTK variants in ClinVar

11 Conditions Cataloged

not providedTotal: 765

MERTK-related disorderTotal: 137

not specifiedTotal: 118

Inborn genetic diseasesTotal: 109

Retinal dystrophyTotal: 87

Retinitis pigmentosa 38Total: 83

Retinitis pigmentosaTotal: 67

Autosomal recessive retinitis pigmentosaTotal: 12

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006343.3. 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		1 clinvar	13 clinvar	181 clinvar		195
missense	4 clinvar	29 clinvar	418 clinvar	33 clinvar	3 clinvar	487
nonsense	21 clinvar	8 clinvar	1 clinvar			30
start loss		1 clinvar				1
frameshift	32 clinvar	14 clinvar	6 clinvar			52
splice donor/acceptor (+/-2bp)	21 clinvar	16 clinvar	4 clinvar			41
Total	78	69	442	214	3	806

Highest pathogenic variant AF is 0.000046481648

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006343.3	RefSeq	NP_006334.2	19	MANE Select
ENST00000295408.9	Ensembl	ENSP00000295408.4	19	MANE Select
ENST00000409780.5	Ensembl	ENSP00000387277.1	17	Standard
ENST00000439966.5	Ensembl	ENSP00000402129.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ebola Virus Pathway on Host
Ebola Virus Pathway on Host
Cell surface interactions at the vascular wall
Hemostasis

Biological Process

natural killer cell differentiation
negative regulation of cytokine production
protein phosphorylation
phagocytosis
cell surface receptor signaling pathway

Molecular Function

transmembrane receptor protein tyrosine kinase activity
protein binding
ATP binding
Wnt-protein binding

Cellular Component

photoreceptor outer segment
extracellular space
cytoplasm
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295408
Coding exons: 19
Length: 131083
Individuals with no LoFs: 125642
Homozygous LoFs: 0
Heterozygous LoFs: 106
Defined: 125748
p: 0.000422

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.588	509	548	0.929	0.0000316	6535
Missense (PolyPhen)		187	197.16	0.94848		2387
Synonymous	0.494	207	216	0.957	0.0000136	1977
Loss of Function	2.94	25	46.7	0.536	0.00000272	526

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.00097	0.00097	rare
European (Non-Finnish)	0.00035	0.00035	rare
South Asian	0.00056	0.00056	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to several ligands including LGALS3, TUB, TULP1 or GAS6. Regulates many physiological processes including cell survival, migration, differentiation, and phagocytosis of apoptotic cells (efferocytosis). Ligand binding at the cell surface induces autophosphorylation of MERTK on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with GRB2 or PLCG2 and induces phosphorylation of MAPK1, MAPK2, FAK/PTK2 or RAC1. MERTK signaling plays a role in various processes such as macrophage clearance of apoptotic cells, platelet aggregation, cytoskeleton reorganization and engulfment. Functions in the retinal pigment epithelium (RPE) as a regulator of rod outer segments fragments phagocytosis. Plays also an important role in inhibition of Toll- like receptors (TLRs)-mediated innate immune response by activating STAT1, which selectively induces production of suppressors of cytokine signaling SOCS1 and SOCS3. {ECO:0000269|PubMed:17005688}.;
Disease: DISEASE: Retinitis pigmentosa 38 (RP38) [MIM:613862]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:11062461}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.244

Intolerance Scores

LoFtool: 0.785
RVIS EVS: 0.87
RVIS percentile EVS: 88.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.603

Gene Damage Prediction

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