LRP5

Gene Facts

• HGNC Symbol: LRP5 (HGNC:6697)
• HGNC Name: LDL receptor related protein 5
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: LRP7, OPPG, EVR1
• Alias symbols: LR3, BMND1, HBM, OPS, OPTA1, VBCH2, EVR4
• %HI: 8.86
• pLI: 0.94
• LOEUF: 0.48
• Cytoband: 11q13.2
• Genomic Coordinates:

  GRCh37/hg19:	chr11:68080059-68216743
  GRCh38/hg38:	chr11:68298412-68449275

• MANE Select Transcript: NM_002335.4 ENST00000294304.12
• Function: Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins (PubMed:11336703, PubMed:11448771, PubMed:15778503, PubMed:11719191, PubMed:15908424, PubMed:16252235). Activates the canonical Wnt signaling pathway that controls cell fate determination and self-renewal during embryonic development and adult tissue regeneration (PubMed:11336703, PubMed:11719191). In particular, may play an important role in the development of t... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-29983
• ClinGen Curation ID: CCID:007419
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/09/2024

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• Familial exudative vitreoretinopathy (FEVR)

HI Evidence

• PUBMED: 15024691
  Toomes et al., (2004) identified six different heterozygous sequence-level LRP5 variants in six unrelated families with familial exudative vitreoretinopathy (FEVR), characterized by the incomplete development of the retinal vasculature and visual impairments that range from mild vision loss to blindness. The FEVR phenotype may result in no overt clinical phenotype, and may only be detected by fluorescein angiography. The variants included one splicing, 1 bp insertion in exon 20 causing frameshift (K1374fsX1549), 1 bp deletion in exon 18 resulting in frameshift (R1270fsX1438), and three missense. The variants were found to segregate with the FEVR phenotype in multiple large families. The splice variant was identified in 7 affected family members and was absent from 3 unaffected family members. The K1374fsX1549 variant segregated with the disease in six individuals in the family but was also found in two asymptomatic family members. One asymptomatic individual with the K1374fsX1549 variant had low bone mass. Of note, these apparently non-penetrant individuals were not evaluated by fluorescein angiography. The K1374fsX1549 variant was not detected in an additional 10 unaffected individuals in this family. Functional/expression studies were not performed; however, these alleles are predicted to result in a loss-of-function. Interestingly, the R1270fsX1438 was reported elsewhere as a homozygous variant in an individual with autosomal recessive osteoporosis–pseudoglioma syndrome (OPPG).
• PUBMED: 34860240
  Tao et al 2021 analyzed 6 known FEVR-associated genes in a cohort of 120 affected individuals. Variants in LRP5 were detected in 31 individuals including 3 nonsense, 2 splice site, and 1 frameshift variant.
• PUBMED: 25711638
  Salvo et al. 2015 sequenced 163 known retinal disease-causing genes in 92 individuals with FEVR. In this cohort, 3 frameshift variants in LRP5 were detected.
• PUBMED: 28867931
  Huang et al. 2017 identified a novel heterozygous 1 bp deletion resulting in frameshift (p.Ile1351IlefsX88) in a severe form of FEVR in a 3-generation family which included three affected individuals.
• PUBMED: 30452590
  Li et al 2018 identified 3 truncating and 1 splice site variant in LRP5 in a cohort of 389 individuals with FEVR. The variants were all noted to segregate with disease, however, no information on the number of individuals tested in each family was provided.
• PUBMED: 35133048
  Zhao et al (2022) identified 4 novel truncating variants in four families with FEVR. In three families the variant was detected in the proband and an affected parent. In one family the variant was detected in an affected parent and three affected offspring. A reporter assay was performed to assess the effect of the variants on canonical Norrin/B-catenin signaling. All 4 truncating variants showed severe reduction similar to the vector control. Western blot showed degradation of the truncated proteins.

• HI Evidence Comments: The low density lipoprotein receptor protein 5 (LRP5) is highly expressed in many tissues including bone, liver, heart, retina, skin, and pancreas during various stages of development. Despite a very potent and diverse signaling network such as the b-catenin pathway, LRP5 is a major player in morphological development, sugar and lipid metabolism. LRP5 encodes a protein also involved in the evolutionary highly conserved Wnt signaling network that plays an important role in eye development and angiogenesis. LRP5 consists of 23 exons and encodes a 1,615–amino acid protein. Its extracellular segment contains four domains, each composed of six YWTD repeats (which form a b-propeller structure) and an epidermal growth factor–like domain (YWTD-EGF domain). These are followed by three low-density-lipoprotein receptor–like (LDL-R–like) ligand-binding domains. Heterozygous sequence-level variants and intragenic deletions in LRP5 have been identified in association with familial exudative vitreoretinopathy-4 (EVR4; FEVR), a hereditary visual impairment disorder. Pathogenic variants in LRP5 have also been associated with two groups of bone abnormalities. The first group includes osteoporosis–pseudoglioma syndrome (OPPG; OMIM 259770), a rare autosomal recessive condition that initiates during early childhood. The major symptoms of OPPG include visual loss due to several vitreoretinal dysplasias and bone weakness that results in multiple fractures and deformities as the bone mass reduces. Carriers of OPPG-associated LRP5 variants are often found to have reduced bone mass density. The second group of diseases comprises endosteal hyperostosis (OMIM 144750), osteosclerosis (OMIM 144750), osteopetrosis (OMIM 607634), van Buchem disease type 2 (VBCH2; OMIM 607636), and highbone mass trait (HBM; OMIM 601884), characterized by a high-bone-mass phenotype and are inherited in autosomal dominant mode. Whereas LRP5 variants that are associated with FEVR are scattered throughout the gene, other pathogenic variants in LRP5 that seem to be clustered locally cause different phenotypes. Individuals suffering from a group of disorders demonstrating high bone mass and sclerosing bone dysplasias, show autosomal dominant missense variants clustered in exons 2 to 5 that encode the first ‘‘b-propeller’’ domain of LRP5. Most LRP5 variants resulting in FEVR are predicted to result in a loss-of-function; however corresponding functional data are lacking and as yet, whole LRP5 gene deletion has not been reported. Furthermore, not all carriers of LRP5 loss-of-function variants exhibit a FEVR phenotype. With consideration for this information, the current evidence in support of haploinsufficiency for this gene is considered to be emerging and the haploinsufficiency score is a 1. Additional references PMID: 20340138 Nikopoulos et al. 2010 reported a novel nonsense variant (p.W993X) in a sporadic patient with FEVR that results in a premature stop codon in exon 13 likely causing NMD and thus leading to LRP5 haploinsufficiency. The authors do not comment on the inheritance of this variant. Two other novel missense and a novel splice site variant (c.4489-1G>A) were also reported in this study. PMID: 29074561 Ellingford et al. 2018 reported a deletion of exon 1 using next generation sequencing in an individual with FEVR (Supplemental Results, Table S5.) PMID: 23077402 Yang et al 2012 sequenced the genes FZD4 and LRP5 in 49 families with FEVR. A frameshift variant was identified in one individual, however, inheritance was not reported. PMID: 34924743 Luo et al 2021 identified a deletion of exons 19-21 in an individual with FEVR. The deletion was found to be inherited from an unaffected father who showed no features of FEVR on fundus examination. Recessive variants in OPPG PMID: 11719191 Gong et al 2001 identified 6 homozygous frameshift or nonsense variants in individuals with OPPG. All heterozygous carriers had low bone mineral density. Eye phenotypes in heterozygotes were not assessed. PMID: 16252235 Ai et al 2005 sequenced LRP5 in 37 families suspected to have OPPG. They identified 11 nonsense, 11 frameshift, 2 splice site, and 20 missense variants in the homozygous or compound heterozygous state. Ten carrier parents underwent ophthalmologic exam and only 2 had subtle evidence of retinal disease.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time there is not evidence to support triplosensitivity.