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FLASH GENE

Symbol

LRP4

contributors: mct/npt/pgu - updated : 12-01-2016

HGNC name	low density lipoprotein receptor-related protein 4
HGNC id	6696

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	CMS17 myasthenic syndrome, congenital, 17 SOST2 sclerosteosis-2
Location	11p11.2      Physical location : 46.878.268 - 46.940.173
Synonym name	multiple epidermal growth factor-like motif 7
Synonym symbol(s)	MEGF7, LRP10, KIAA0816

DNA

TYPE	functioning gene
STRUCTURE	61.66 kb     38 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002334 38 - 7998 NP_002325 - 1905 - 2008 18957220

EXPRESSION

Type

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive intestine small intestine     moderately   intestine large intestine colon   highly Endocrine thyroid       predominantly Hearing/Equilibrium ear inner cochlea   moderately Nervous brain forebrain cerebral cortex   highly Homo sapiens   brain limbic system hippocampus     Homo sapiens   brain hindbrain cerebellum     Homo sapiens   nerve       highly Homo sapiens Olfactory (smell) olfactory bulb         Homo sapiens Skeleton           Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Skeleton osteoblast Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	eight LDL-receptor class A domains
	two calcium binding type EGF-like motif
	twenty LDL-receptor class B repeats
	a extracellular beta-propeller structured domain required for the sclerostin facilitator activity
	an EGF-like motifs
	a cytoplasmic domain having important signaling and/or anchoring functions in certain tissues but not at neuromuscular synapses

conjugated

GlycoP

isoforms

Precursor

a 17 aa signal peptide of 1.9 kda and a 1888 aa mature peptide of 210.1 kda

HOMOLOGY

interspecies	homolog to rattus Lrp4 (96.4 pc)
	homolog to murine Lrp4 (96.6 pc)

intraspecies

homolog to low density lipoprotein receptor 4 (LDLR)

Homologene

FAMILY

LDLR family

CATEGORY

receptor membrane

SUBCELLULAR LOCALIZATION	plasma membrane
text	type II membrane anchored protein

basic FUNCTION	acting as a potential cell surface endocytic receptor which binds and internalizes extracellular ligands for degradation by lysosomes
	receptor for Agrin, which forms a complex with MUSK, and mediates MUSK activation by Agrin
	can binds ligands that are structurally akin to AGRN and associates with other receptor tyrosine kinases, like MUSK, in these tissues
	important for control and modification of Wnt signaling by its antagonistic effect on LRP6-mediated activation of WNT signaling
	multi-functional receptor implicated in the regulation of several molecular pathways, including Wnt and Bmp signaling
	specifically facilitates the previously described inhibitory action of sclerostin on WNT1/CTNNB signaling
	functions as a direct muscle-derived retrograde signal for early steps in presynaptic differentiation
	acts bi-directionally and coordinates synapse formation by binding Agrin, activating MUSK and stimulating postsynaptic differentiation
	LRP4 and MUSK act as scaffolds for multiple binding partners, resulting in a complex and dynamic network of interacting proteins that is required for ACHR clustering

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

endocytosis transport

PATHWAY

metabolism

signaling

a component

LRP4 and MUSK can interact and form a complex

INTERACTION

DNA

RNA

small molecule	metal binding, nucleotide,
	Ca2+

protein	AGRN receptor
	sclerostin (SOST) interaction partner (interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone)
	AGRN binds LRP4 and stimulates further MUSK phosphorylation, stabilizing nascent synapses
	cis-acting ligand for MUSK, whereas AGRN functions as an allosteric and paracrine regulator to promote association between LRP4 and MUSK
	interplay between LRP4 and SOSTDC1 in inhibiting Wnt/CTNNB1 signaling, providing an insight into how modulation of Wnt/CTNNB1 signaling controls cellular processes important for skin placode formation
	ligand for MUSK, and binding affinity for MUSK is potentiated by agrin, a neuronally derived heparan-sulfate proteoglycan 9)
	MESD binds to the intracellular form of LRP4 and promotes its glycosylation and cell-surface expression
	COLQ binds directly to LRP4 but not to MUSK and COLQ interacts indirectly with MUSK through LRP4
	LRP4 is a major receptor of COLQ

cell & other

REGULATION

ASSOCIATED DISORDERS

corresponding disease(s)

SDTY7 , SOST2 , CMS17

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation       associated with bone overgrowth and impaired sclerostin facilitator function

Susceptibility

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

	polysyndactyly caused by two recessive mutations in the mouse Lrp4 gene
	syndactyly caused by mutations in the bovine Lrp4 gene
	Lrp4 mutant mice displayed a delay in placode initiation and changes in distribution and number of mammary precursor cells leading to abnormal morphology, number and position of mammary placodes
	Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis
	Lrp4 null mutations in mice result in limb development defects and in perinatal death due to a lack of neuromuscular junction formation