LRP4

LDL receptor related protein 4, the group of Low density lipoprotein receptors

Basic information

Region (hg38): 11:46856716-46918642

Links

ENSG00000134569 ∙ NCBI:4038 ∙ OMIM:604270 ∙ HGNC:6696 ∙ Uniprot:O75096 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Cenani-Lenz syndactyly syndrome (Definitive), mode of inheritance: AR
• congenital myasthenic syndrome 17 (Strong), mode of inheritance: AR
• congenital myasthenic syndrome 17 (Strong), mode of inheritance: AR
• sclerosteosis 2 (Limited), mode of inheritance: Semidominant
• Cenani-Lenz syndactyly syndrome (Strong), mode of inheritance: AR
• sclerosteosis (Supportive), mode of inheritance: AR
• Cenani-Lenz syndactyly syndrome (Supportive), mode of inheritance: AR
• postsynaptic congenital myasthenic syndrome (Supportive), mode of inheritance: AR
• congenital myasthenic syndrome 17 (Limited), mode of inheritance: AR
• Cenani-Lenz syndactyly syndrome (Strong), mode of inheritance: AR
• Cenani-Lenz syndactyly syndrome (Definitive), mode of inheritance: AR
• congenital myasthenic syndrome 17 (Limited), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cenani-Lenz syndactyly syndrome; Myasthenic syndrome, congenital 17; Sclerosteosis 2	AD/AR	General	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	Craniofacial; Musculoskeletal; Neurologic; Renal	7891385; 9182770; 10756427; 11260233; 11385236; 14577675; 12868467; 18978656; 20381006; 21471202; 24234652
In Myasthenic syndrome, congenital, treatment with cholinesterase inhibitor was not effective

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LRP4 gene.

• Cenani-Lenz syndactyly syndrome;Sclerosteosis 2;Congenital myasthenic syndrome 17 (255 variants)
• not provided (194 variants)
• Cenani-Lenz syndactyly syndrome (170 variants)
• Sclerosteosis 2;Cenani-Lenz syndactyly syndrome;Congenital myasthenic syndrome 17 (141 variants)
• Sclerosteosis 2;Congenital myasthenic syndrome 17;Cenani-Lenz syndactyly syndrome (126 variants)
• Congenital myasthenic syndrome 17;Cenani-Lenz syndactyly syndrome;Sclerosteosis 2 (120 variants)
• Cenani-Lenz syndactyly syndrome;Congenital myasthenic syndrome 17;Sclerosteosis 2 (100 variants)
• Congenital myasthenic syndrome 17;Sclerosteosis 2;Cenani-Lenz syndactyly syndrome (78 variants)
• Inborn genetic diseases (67 variants)
• not specified (20 variants)
• Congenital myasthenic syndrome 17 (11 variants)
• Sclerosteosis 2 (9 variants)
• LRP4-related condition (5 variants)
• Bone Mineral Density Variation (2 variants)
• Abnormality of the musculature (1 variants)
• LRP4-Related Disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LRP4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			10	205	6	221
missense		2	438	9	4	453
nonsense	3	1	2			6
start loss						0
frameshift	1	1	2			4
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1	4				5
splice region			26	33		59
non coding			40	119	64	223
Total	5	8	495	333	74

Highest pathogenic variant AF is 0.0000197

Variants in LRP4

This is a list of pathogenic ClinVar variants found in the LRP4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
11-46856731-C-T		Cenani-Lenz syndactyly syndrome	Benign (Apr 27, 2017)
11-46856771-G-A		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46856879-G-C		Cenani-Lenz syndactyly syndrome	Likely benign (Apr 27, 2017)
11-46856900-C-CA		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jun 14, 2016)
11-46856903-A-G		Cenani-Lenz syndactyly syndrome	Benign (Apr 27, 2017)
11-46856929-G-A		Cenani-Lenz syndactyly syndrome	Likely benign (Jan 12, 2018)
11-46857156-TAC-T		Cenani-Lenz syndactyly syndrome	Likely benign (Jun 14, 2016)
11-46857256-C-T		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 12, 2018)
11-46857321-G-T		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46857356-T-C		Cenani-Lenz syndactyly syndrome	Benign (Apr 27, 2017)
11-46857397-A-C		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46857437-G-A		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46857516-G-A		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46857538-T-C		Cenani-Lenz syndactyly syndrome	Benign (Apr 27, 2017)
11-46857648-C-T		Cenani-Lenz syndactyly syndrome	Uncertain significance (Apr 27, 2017)
11-46857648-C-CA		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jun 14, 2016)
11-46857661-C-A		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 13, 2018)
11-46857710-C-G		Cenani-Lenz syndactyly syndrome	Uncertain significance (Feb 09, 2018)
11-46857832-G-A		Cenani-Lenz syndactyly syndrome	Benign (Jan 12, 2018)
11-46857919-G-C		Cenani-Lenz syndactyly syndrome	Uncertain significance (Jan 12, 2018)
11-46857966-G-A		Cenani-Lenz syndactyly syndrome	Benign (Apr 27, 2017)
11-46858054-G-T		Cenani-Lenz syndactyly syndrome	Likely benign (Apr 27, 2017)
11-46858062-T-G		Cenani-Lenz syndactyly syndrome	Uncertain significance (Apr 27, 2017)
11-46858203-G-A		Cenani-Lenz syndactyly syndrome	Uncertain significance (Apr 27, 2017)
11-46858249-G-C		Cenani-Lenz syndactyly syndrome	Uncertain significance (Apr 27, 2017)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LRP4	protein_coding	protein_coding	ENST00000378623	38	61775

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00000144	1.00	125683	0	65	125748	0.000258

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.06	832	1.12e+3	0.742	0.0000764	12584
Missense in Polyphen		213	381.29	0.55863		4199
Synonymous	-0.313	439	431	1.02	0.0000286	3673
Loss of Function	6.36	30	97.9	0.307	0.00000554	1052

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000325	0.000325
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.000218	0.000217
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000337	0.000334
Middle Eastern	0.000218	0.000217
South Asian	0.000392	0.000392
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mediates SOST-dependent inhibition of bone formation. Functions as a specific facilitator of SOST-mediated inhibition of Wnt signaling. Plays a key role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between motor neuron and skeletal muscle. Directly binds AGRIN and recruits it to the MUSK signaling complex. Mediates the AGRIN- induced phosphorylation of MUSK, the kinase of the complex. The activation of MUSK in myotubes induces the formation of NMJ by regulating different processes including the transcription of specific genes and the clustering of AChR in the postsynaptic membrane. Alternatively, may be involved in the negative regulation of the canonical Wnt signaling pathway, being able to antagonize the LRP6-mediated activation of this pathway. More generally, has been proposed to function as a cell surface endocytic receptor binding and internalizing extracellular ligands for degradation by lysosomes. May play an essential role in the process of digit differentiation (By similarity). {ECO:0000250|UniProtKB:Q8VI56, ECO:0000269|PubMed:20381006, ECO:0000269|PubMed:21471202}.
• Disease: DISEASE: Sclerosteosis 2 (SOST2) [MIM:614305]: A sclerosing bone dysplasia characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. {ECO:0000269|PubMed:21471202, ECO:0000269|PubMed:24234652}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myasthenic syndrome, congenital, 17 (CMS17) [MIM:616304]: A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. {ECO:0000269|PubMed:24234652}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Extracellular matrix organization;ECM proteoglycans (Consensus)

Recessive Scores

• pRec: 0.170

Intolerance Scores

• loftool: 0.0317
• rvis_EVS: -1.33
• rvis_percentile_EVS: 4.69

Haploinsufficiency Scores

• pHI: 0.571
• hipred: Y
• hipred_score: 0.575
• ghis: 0.528

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.824

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Lrp4
• Phenotype: embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; homeostasis/metabolism phenotype; skeleton phenotype; renal/urinary system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype; craniofacial phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: lrp4
• Affected structure: muscle
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: kidney development;hair follicle development;endocytosis;dorsal/ventral pattern formation;proximal/distal pattern formation;Wnt signaling pathway;negative regulation of ossification;BMP signaling pathway;odontogenesis of dentin-containing tooth;embryonic digit morphogenesis;dendrite morphogenesis;positive regulation of peptidyl-tyrosine phosphorylation;negative regulation of axonogenesis;synapse organization;synaptic growth at neuromuscular junction;protein heterotetramerization;limb development;skeletal muscle acetylcholine-gated channel clustering;negative regulation of canonical Wnt signaling pathway;postsynaptic membrane assembly;presynaptic membrane assembly;positive regulation of presynaptic membrane organization;positive regulation of skeletal muscle acetylcholine-gated channel clustering
• Cellular component: plasma membrane;cell surface;postsynaptic density;integral component of membrane;dendrite;neuromuscular junction;neuronal cell body;plasma membrane raft;synaptic membrane
• Molecular function: calcium ion binding;protein binding;receptor tyrosine kinase binding;apolipoprotein binding;protein homodimerization activity;scaffold protein binding