LRP2LDL receptor related protein 2
Autism Reports / Total Reports
13 / 20Rare Variants / Common Variants
49 / 12Aliases
LRP2, DBS, GP330Associated Syndromes
Donnai-Barrow syndrome, DDChromosome Band
2q31.1Associated Disorders
ASD, EPS, IDRelevance to Autism
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2 10(-5)). (Ionita-Laza et al., 2012). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (Iossifov et al., 2012).
Molecular Function
The protein encoded by this gene, low density lipoprotein-related protein 2 (LRP2) or megalin, is a multi-ligand endocytic receptor that is expressed in many different tissues but primarily in absorptive epithilial tissues such as the kidney. This glycoprotein has a large amino-terminal extracellular domain, a single transmembrane domain, and a short carboxy-terminal cytoplasmic tail. The extracellular ligand-binding-domains bind diverse macromolecules including albumin, apolipoproteins B and E, and lipoprotein lipase. The LRP2 protein is critical for the reuptake of numerous ligands, including lipoproteins, sterols, vitamin-binding proteins, and hormones. This protein also has a role in cell-signaling; extracellular ligands include parathyroid horomones and the morphogen sonic hedgehog while cytosolic ligands include MAP kinase scaffold proteins and JNK interacting proteins. Recycling of this membrane receptor is regulated by phosphorylation of its cytoplasmic domain.
External Links
SFARI Genomic Platforms
Reports related to LRP2 (20 Reports)
# | Type | Title | Author, Year | Autism Report | Associated Disorders |
---|---|---|---|---|---|
1 | Highly Cited | Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes | Kantarci S , et al. (2007) | No | - |
2 | Support | De novo gene disruptions in children on the autistic spectrum | Iossifov I , et al. (2012) | Yes | - |
3 | Primary | Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three datasets | Ionita-Laza I , et al. (2012) | Yes | - |
4 | Support | Diagnostic exome sequencing in persons with severe intellectual disability | de Ligt J , et al. (2012) | No | Epilepsy, ASD |
5 | Support | Synaptic, transcriptional and chromatin genes disrupted in autism | De Rubeis S , et al. (2014) | Yes | - |
6 | Support | Large-scale discovery of novel genetic causes of developmental disorders | Deciphering Developmental Disorders Study (2014) | No | Microcephaly, hearing impairment |
7 | Recent Recommendation | Integrated systems analysis reveals a molecular network underlying autism spectrum disorders | Li J , et al. (2015) | Yes | - |
8 | Support | Excess of rare, inherited truncating mutations in autism | Krumm N , et al. (2015) | Yes | - |
9 | Positive Association | Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population | Kuo PH , et al. (2015) | Yes | - |
10 | Support | Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism | Chen R , et al. (2017) | Yes | - |
11 | Support | Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families | Harripaul R , et al. (2017) | No | - |
12 | Support | Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes | Feliciano P et al. (2019) | Yes | - |
13 | Support | Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy | Lee J et al. (2020) | Yes | ID, epilepsy/seizures |
14 | Support | - | Mitani T et al. (2021) | No | - |
15 | Support | - | Mahjani B et al. (2021) | Yes | - |
16 | Support | - | Woodbury-Smith M et al. (2022) | Yes | - |
17 | Support | - | Hu C et al. (2022) | Yes | - |
18 | Support | - | Zhou X et al. (2022) | Yes | - |
19 | Support | - | Alessia Mingarelli et al. (2023) | No | Autistic features, stereotypy, epilepsy/seizures |
20 | Support | - | M Cecilia Poli et al. () | No | - |
Rare Variants (49)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
- | - | nonsynonymous_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.8452+1G>A | - | splice_site_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
- | p.(=) | synonymous_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.100C>T | p.Arg34Cys | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2320G>T | p.Gly774Ter | stop_gained | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
c.10393+1G>A | - | splice_site_variant | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
c.4692-35G>C | - | intron_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.10836G>T | p.Gln3612His | missense_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
c.5314G>A | p.Val1772Ile | missense_variant | Unknown | - | - | 32477112 | Lee J et al. (2020) | |
c.3371A>G | p.Lys1124Arg | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.4403T>C | p.Ile1468Thr | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.4878T>A | p.Asp1626Glu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.4927C>T | p.Arg1643Trp | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.9911G>T | p.Arg3304Leu | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.12926T>A | p.Leu4309Gln | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.2772G>A | p.Glu924%3D | synonymous_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.149C>G | p.Thr50Ser | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.775G>C | p.Gly259Arg | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.2933C>T | p.Thr978Met | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.9929G>A | p.Arg3310His | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.11107G>A | p.Asp3703Asn | missense_variant | Unknown | - | Unknown | 25549968 | Li J , et al. (2015) | |
c.4234C>T | p.Arg1412Trp | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
c.9550C>T | p.Arg3184Ter | stop_gained | De novo | - | Simplex | 22542183 | Iossifov I , et al. (2012) | |
c.10887C>G | p.His3629Gln | missense_variant | De novo | - | - | 25363760 | De Rubeis S , et al. (2014) | |
c.2944G>T | p.Gly982Cys | missense_variant | De novo | - | Simplex | 34582790 | Mitani T et al. (2021) | |
c.1093C>T | p.Arg365Ter | stop_gained | Familial | Paternal | - | 31452935 | Feliciano P et al. (2019) | |
c.4766G>A | p.Arg1589His | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.4979G>A | p.Arg1660His | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.5792A>G | p.Gln1931Arg | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.5842G>A | p.Val1948Met | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.5932G>C | p.Glu1978Gln | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.6049G>A | p.Glu2017Lys | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.6160G>A | p.Asp2054Asn | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.10887C>G | p.His3629Gln | missense_variant | De novo | - | Simplex | 28344757 | Chen R , et al. (2017) | |
c.12137G>A | p.Arg4046Gln | missense_variant | De novo | - | Simplex | 25961944 | Krumm N , et al. (2015) | |
c.7931T>A | p.Val2644Glu | missense_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
c.11938A>G | p.Thr3980Ala | missense_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
c.5406_5407del | p.His1802GlnfsTer39 | frameshift_variant | Unknown | - | - | 35741772 | Hu C et al. (2022) | |
c.12437del | p.Gly4146GlufsTer2 | frameshift_variant | De novo | - | - | 23033978 | de Ligt J , et al. (2012) | |
c.11469_11472del | p.Cys3823TrpfsTer159 | frameshift_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.11503C>T | p.Arg3835Cys | missense_variant | Familial | Both parents | - | 38177409 | M Cecilia Poli et al. () | |
NM_004525.2:4978C>T | p.Arg1660Cys | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
NM_004525:c.6256G>C | p.Thr2086Ser | missense_variant | Unknown | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.11335G>A | p.Asp3779Asn | missense_variant | Familial | Both parents | Multiplex | 28397838 | Harripaul R , et al. (2017) | |
c.6815G>A | p.Arg2272His | missense_variant | Familial | Maternal | Multiplex (monozygotic twins) | 37810913 | Alessia Mingarelli et al. (2023) | |
c.12725A>G | p.Asp4242Gly | missense_variant | Familial | Paternal | Multiplex (monozygotic twins) | 37810913 | Alessia Mingarelli et al. (2023) | |
c.5209C>T | p.Leu1737Phe | missense_variant | Familial | Maternal and Paternal | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.6160G>A | p.Asp2054Asn | missense_variant | Familial | Maternal and Paternal | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) | |
c.11663G>A | p.Arg3888His | missense_variant | Familial | Maternal and Paternal | Simplex | 25533962 | Deciphering Developmental Disorders Study (2014) |
Common Variants (12)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Paternal Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.4875T>C;c.2586T>C;c.4890T>C;c.2601T>C | p.(=) | synonymous_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.4294+19C>T;c.2005+19C>T;c.4309+19C>T;c.2020+19C>T | - | intron_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.5825T>G;c.3536T>G;c.5840T>G;c.3551T>G | p.Val1942Gly;p.Val1179Gly;p.Val1947Gly;p.Val1184Gly | missense_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
- | - | intergenic_variant | - | - | - | 26398136 | Kuo PH , et al. (2015) | |
- | - | gene_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3550+14C>T;c.1261+14C>T | - | intron_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3550+18T>G;c.1261+18T>G | - | intron_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3667+20A>C;c.1378+20A>C | - | intron_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.2460A>G;c.171A>G | p.(=) | synonymous_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3054C>A;c.765C>A | p.(=) | synonymous_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3069A>G;c.780A>G | p.(=) | synonymous_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) | |
c.3660A>G;c.1371A>G | p.(=) | synonymous_variant | - | - | - | 22578327 | Ionita-Laza I , et al. (2012) |
SFARI Gene score
Strong Candidate
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
4/1/2022
Decreased from 3 to 2
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
4/1/2020
Decreased from 3 to 3
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
10/1/2019
Decreased from 4 to 3
New Scoring Scheme
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
4/1/2017
Decreased from 4 to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three...2012] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.2007] [Excess of rare, inherited truncating mutations in autism.2015] [Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism.2017] [Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguin...2017]1/1/2016
Decreased from 4 to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Scan-statistic approach identifies clusters of rare disease variants in LRP2, a gene linked and associated with autism spectrum disorders, in three...2012] [Integrated systems analysis reveals a molecular network underlying autism spectrum disorders.2015] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.2007] [Excess of rare, inherited truncating mutations in autism.2015] [Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]4/1/2015
Decreased from 4 to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
1/1/2015
Decreased from 4 to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
7/1/2014
Increased from No data to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
4/1/2014
Increased from No data to 4
Description
Cluster-detection analysis of an ASD-associated chromosome 2q linkage region that had been sequenced in three independent datasets revealed variants in the LRP2 gene that were associated with ASD in two of the datasets (the combined variable-threshold-test p value is 1.2?? 10(-5)) (PMID 22578327). A de novo nonsense variant in the LRP2 gene was identified in an autistic proband following exome sequencing of 343 quad families from the Simons Simplex Collection (PMID 22542183).
Krishnan Probability Score
Score 0.57186013343073
Ranking 745/25841 scored genes
[Show Scoring Methodology]
ExAC Score
Score 0.99999999999851
Ranking 42/18225 scored genes
[Show Scoring Methodology]
Sanders TADA Score
Score 0.77734812763312
Ranking 1866/18665 scored genes
[Show Scoring Methodology]
Larsen Cumulative Evidence Score
Score 43
Ranking 45/461 scored genes
[Show Scoring Methodology]
Zhang D Score
Score -0.020202855002811
Ranking 9357/20870 scored genes
[Show Scoring Methodology]
External PIN Data
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
---|---|---|---|---|---|
Alb | albumin | Rat | Protein Binding | 24186 | P02770 |
AMBN | Ameloblastin | Human | Protein Binding | 258 | Q9NP70-2 |
APOH | apolipoprotein H (beta-2-glycoprotein I) | Human | Protein Binding | 350 | P02749 |
DLK2 | Protein delta homolog 2 | Human | Protein Binding | 65989 | Q6UY11-2 |
FAM19A3 | Protein FAM19A3 | Human | Protein Binding | 284467 | Q7Z5A8-2 |
FAM19A4 | Protein FAM19A4 | Human | Protein Binding | 151647 | Q96LR4 |
Fut4 | fucosyltransferase 4 | Mouse | Direct Regulation | 14345 | Q11127 |
GC | Vitamin D-binding protein | Rabbit | Protein Binding | 100008994 | P53789 |
INSL6 | Insulin-like peptide INSL6 | Human | Protein Binding | 11172 | Q9Y581 |
LCN2 | lipocalin 2 | Human | Protein Binding | 3934 | P80188 |
Ldlrap1 | low density lipoprotein receptor adaptor protein 1 | Rat | Protein Binding | 500564 | D3ZAR1 |
LPA | lipoprotein, Lp(a) | Human | Protein Binding | 4018 | P08519 |
LRP2BP | LRP2 binding protein | Human | Protein Binding | 55805 | Q9P2M1 |
Lyz2 | lysozyme 2 | Rat | Protein Binding | 25211 | Q6PDV1 |
MEPE | Matrix extracellular phosphoglycoprotein | Human | Protein Binding | 56955 | Q9NQ76 |
NHE-3 | Sodium/hydrogen exchanger 3 | Rabbit | Protein Binding | 100009430 | P26432 |
PDGFD | Platelet-derived growth factor D | Human | Protein Binding | 80310 | Q9GZP0-2 |
PLAU | plasminogen activator, urokinase | Human | Protein Binding | 5328 | P00749 |
RBP1 | retinol binding protein 1, cellular | Human | Protein Binding | 5947 | P09455 |
RIBC2 | RIB43A-like with coiled-coils protein 2 | Human | Protein Binding | 26150 | Q9H4K1 |
Tg | thyroglobulin | Rat | Protein Binding | 24826 | G3V6V3 |
VIP | VIP peptides | Human | Protein Binding | 7432 | P01282 |
ZFP41 | Zinc finger protein 41 homolog | Human | Protein Binding | 286128 | Q8N8Y5 |