Human Gene Module / Chromosome 2 / LRP2

LRP2LDL receptor related protein 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 20
Rare Variants / Common Variants
49 / 12
Aliases
LRP2, DBS,  GP330
Associated Syndromes
Donnai-Barrow syndrome, DD
Chromosome Band
2q31.1
Associated Disorders
ASD, EPS, ID
Relevance 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.

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 - et al. () No Autistic features, stereotypy, epilepsy/seizures
20 Support - 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.11503C>T p.Arg3835Cys missense_variant Familial Both parents - 38177409 et al. ()
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)
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.6815G>A p.Arg2272His missense_variant Familial Maternal Multiplex (monozygotic twins) 37810913 et al. ()
c.12725A>G p.Asp4242Gly missense_variant Familial Paternal Multiplex (monozygotic twins) 37810913 et al. ()
c.11335G>A p.Asp3779Asn missense_variant Familial Both parents Multiplex 28397838 Harripaul R , et al. (2017)
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
2

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

2

Strong Candidate

See all Category 2 Genes

We 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
3
icon
2

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
3
icon
3

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
4
icon
3

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
4
icon
4

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).

4/1/2015
4
icon
4

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
4
icon
4

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
No data
icon
4

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
No data
icon
4

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]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999999999851

Ranking 42/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.77734812763312

Ranking 1866/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 43

Ranking 45/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score -0.020202855002811

Ranking 9357/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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
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