MESP2

protein-coding

mesoderm posterior bHLH transcription factor 2, the group of Basic helix-loop-helix proteins

Gene summary

This gene encodes a member of the bHLH family of transcription factors and plays a key role in defining the rostrocaudal patterning of somites via interactions with multiple Notch signaling pathways. This gene is expressed in the anterior presomitic mesoderm and is downregulated immediately after the formation of segmented somites. This gene also plays a role in the formation of epithelial somitic mesoderm and cardiac mesoderm. Mutations in the MESP2 gene cause autosomal recessive spondylocostal dystosis 2 (SCD02). [provided by RefSeq, Oct 2008]

MANE transcript

NM_001039958.2

Inheritance

ClinVar variants

P:85U:163B:279

Top phenotype

Spondylocostal dysostosis 2, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr15:89,760,591-89,778,754

External References & Databases

Ensembl (ENSG00000188095)

Transcript & Mutation Effects

hg38 • Region Span ~18.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spondylocostal dysostosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010180

Submitter: Orphanet

spondylocostal dysostosis 2, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012097

Submitter: Labcorp Genetics (formerly Invitae)

spondylocostal dysostosis 2, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012097

Submitter: PanelApp Australia

spondylocostal dysostosis 2, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012097

Submitter: G2P

spondylocostal dysostosis 2, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012097

Submitter: Natera

Clinical Genomic Database (CGD)

Spondylocostal dysostosis 2, autosomal recessiveAR

Manifestation: Musculoskeletal

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: 15214000; 15122512; 18485326; 20301771

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MESP2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 405

Spondylocostal dysostosis 2, autosomal recessiveTotal: 169

Inborn genetic diseasesTotal: 67

not specifiedTotal: 31

MESP2-related disorderTotal: 14

MESP2-related disordersTotal: 1

Spondylocostal dysostosis 1, autosomal recessiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001039958.2. 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			6 clinvar	259 clinvar	2 clinvar	267
missense			136 clinvar	14 clinvar	4 clinvar	154
nonsense	17 clinvar	17 clinvar	7 clinvar			41
start loss		3 clinvar				3
frameshift	20 clinvar	28 clinvar	13 clinvar			61
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	37	48	163	273	6	527

Highest pathogenic variant AF is 0.0022136138

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001039958.2	RefSeq	NP_001035047.1	2	MANE Select
ENST00000341735.5	Ensembl	ENSP00000342392.3	2	MANE Select
ENST00000560219.2	Ensembl	ENSP00000452998.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mespab	Danio rerio	Structure: determination of heart left/right asymmetry Quality: decreased efficacy abnormal

Gene / Model

Organism

Observed Phenotype

mespab

Danio rerio

Structure: determination of heart left/right asymmetry

Quality: decreased efficacy

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac Progenitor Differentiation
Gene regulatory network modelling somitogenesis

Biological Process

mesoderm formation
somitogenesis
heart morphogenesis
Notch signaling pathway
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
protein dimerization activity

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341735
Coding exons: 2
Length: 18161
Individuals with no LoFs: 124731
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 124751
p: 0.0000802

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.187	204	212	0.964	0.0000119	2438
Missense (PolyPhen)		34	38.671	0.87922		550
Synonymous	-0.0161	103	103	1.00	0.00000656	873
Loss of Function	0.834	10	13.3	0.753	5.88e-7	132

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000067	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00057	0.00056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000066	0.000062	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor with important role in somitogenesis. Defines the rostrocaudal patterning of the somite by participating in distinct Notch pathways. Regulates also the FGF signaling pathway. Specifies the rostral half of the somites. Generates rostro-caudal polarity of somites by down-regulating in the presumptive rostral domain DLL1, a Notch ligand. Participates in the segment border formation by activating in the anterior presomitic mesoderm LFNG, a negative regulator of DLL1-Notch signaling. Acts as a strong suppressor of Notch activity. Together with MESP1 is involved in the epithelialization of somitic mesoderm and in the development of cardiac mesoderm.;
Disease: DISEASE: Spondylocostal dysostosis 2, autosomal recessive (SCDO2) [MIM:608681]: A condition of variable severity associated with vertebral and rib segmentation defects. The main skeletal malformations include fusion of vertebrae, hemivertebrae, fusion of certain ribs, and other rib malformations. Deformity of the chest and spine (severe scoliosis, kyphoscoliosis and lordosis) is a natural consequence of the malformation and leads to a dwarf- like appearance. As the thorax is small, infants frequently have respiratory insufficiency and repeated respiratory infections resulting in life-threatening complications in the first year of life. {ECO:0000269|PubMed:15122512}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.141

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.125

Gene Damage Prediction

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