Human Gene Module / Chromosome 12 / LRP1

LRP1LDL receptor related protein 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 11
Rare Variants / Common Variants
47 / 0
Aliases
LRP1, A2MR,  APOER,  APR,  CD91,  IGFBP-3R,  IGFBP3R,  IGFBP3R1,  KPA,  LRPA,  TGFBR5, LRP1
Associated Syndromes
-
Chromosome Band
12q13.3
Associated Disorders
SCZ
Relevance to Autism

De novo missense variants in the LRP1 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (DeRubeis et al., 2014; Iossifov et al., 2014). Whole-exome sequencing of 20 high-functioning autism families in Torrico et al., 2019 identified a de novo splice-site variant in LRP1 that resulted in in-frame skipping of exon 29 and reduced cytokine expression in proband-derived immortalized lymphocyte cell lines. Torrico et al., 2019 also demonstrated that de novo variants in LRP1 are associated with ASD (P=0.039) and schizophrenia (P=0.008), common variants in LRP1 show gene-based association in schizophrenia (P=6.6E-07) and in a meta-analysis across seven psychiatric disorders (P=1.2E-05), and LRP1 exhibits an increased burden of ultra-rare pathogenic variants in a cohort of ASD probands from the ARRA Autism Sequencing Collaboration compared to controls (35 variants in 1778 ASD probands vs. 64 variants in 7875 controls; P-value of 1.2E-05).

Molecular Function

This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to LRP1 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes Torrico B , et al. (2019) Yes SCZ
4 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Wilfert AB et al. (2021) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Wang J et al. (2023) Yes -
9 Support - Tuncay IO et al. (2023) Yes -
10 Support - Cirnigliaro M et al. (2023) Yes -
11 Support - Suhua Chang et al. () Yes -
Rare Variants   (47)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4362-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.4390G>A p.Asp1464Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8104G>A p.Ala2702Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.8914C>T p.Arg2972Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.10847A>G p.Asp3616Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.11819G>A p.Arg3940His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.12051G>C p.Trp4017Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.7785T>A p.Ser2595%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.430G>C p.Asp144His missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.3998C>T p.Thr1333Ile missense_variant De novo - - 37492102 Tuncay IO et al. (2023)
c.1364G>A p.Arg455Gln missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
A>AG p.Glu104GluTer frameshift_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.408C>G p.Asn136Lys missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.4446T>A p.Phe1482Leu missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.5144A>G p.Lys1715Arg missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.5674T>C p.Phe1892Leu missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.5875G>A p.Val1959Met missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.6214C>T p.Arg2072Trp missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.6394G>A p.Val2132Met missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.6498C>G p.Cys2166Trp missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.6923C>T p.Thr2308Met missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.7542C>G p.Asp2514Glu missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.8104G>A p.Ala2702Thr missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.8936C>T p.Thr2979Met missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.9136G>A p.Gly3046Arg missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.9395A>G p.Asn3132Ser missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.9434G>A p.Arg3145His missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.10274G>A p.Arg3425His missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.11432C>G p.Ser3811Trp missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.11954C>T p.Ala3985Val missense_variant Unknown - - 31094488 Torrico B , et al. (2019)
c.180C>T p.Ala60%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.8719T>A p.Ser2907Thr missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5008C>T p.Arg1670Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.9379G>T p.Glu3127Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.11452G>A p.Gly3818Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.10023C>G p.Cys3341Trp missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1083C>T p.Leu361%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3901G>T p.Ala1301Ser missense_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.13339C>T p.Arg4447Ter stop_gained Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.9144C>T p.Asn3048%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.11925C>T p.Thr3975= synonymous_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.4966G>T p.Asp1656Tyr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.10424G>A p.Arg3475Gln missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.10190A>G p.Asn3397Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.5203A>G p.Thr1735Ala splice_site_variant De novo - Simplex 31094488 Torrico B , et al. (2019)
c.7344_7354del p.His2448GlnfsTer27 frameshift_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.11935_11936del p.Asp3980CysfsTer3 frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants in the LRP1 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (DeRubeis et al., 2014; Iossifov et al., 2014). Whole-exome sequencing of 20 high-functioning autism families in Torrico et al., 2019 identified a de novo splice-site variant in LRP1 that resulted in in-frame skipping of exon 29 and reduced cytokine expression in proband-derived immortalized lymphocyte cell lines. Torrico et al., 2019 also demonstrated that de novo variants in LRP1 are associated with ASD (P=0.039) and schizophrenia (P=0.008), common variants in LRP1 show gene-based association in schizophrenia (P=6.6E-07) and in a meta-analysis across seven psychiatric disorders (P=1.2E-05), and LRP1 exhibits an increased burden of ultra-rare pathogenic variants in a cohort of ASD probands from the ARRA Autism Sequencing Collaboration compared to controls (35 variants in 1778 ASD probands vs. 64 variants in 7875 controls; P-value of 1.2E-05).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo missense variants in the LRP1 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (DeRubeis et al., 2014; Iossifov et al., 2014). Whole-exome sequencing of 20 high-functioning autism families in Torrico et al., 2019 identified a de novo splice-site variant in LRP1 that resulted in in-frame skipping of exon 29 and reduced cytokine expression in proband-derived immortalized lymphocyte cell lines. Torrico et al., 2019 also demonstrated that de novo variants in LRP1 are associated with ASD (P=0.039) and schizophrenia (P=0.008), common variants in LRP1 show gene-based association in schizophrenia (P=6.6E-07) and in a meta-analysis across seven psychiatric disorders (P=1.2E-05), and LRP1 exhibits an increased burden of ultra-rare pathogenic variants in a cohort of ASD probands from the ARRA Autism Sequencing Collaboration compared to controls (35 variants in 1778 ASD probands vs. 64 variants in 7875 controls; P-value of 1.2E-05).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
icon
3

Increased from to 3

Description

De novo missense variants in the LRP1 gene have been observed in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection (DeRubeis et al., 2014; Iossifov et al., 2014). Whole-exome sequencing of 20 high-functioning autism families in Torrico et al., 2019 identified a de novo splice-site variant in LRP1 that resulted in in-frame skipping of exon 29 and reduced cytokine expression in proband-derived immortalized lymphocyte cell lines. Torrico et al., 2019 also demonstrated that de novo variants in LRP1 are associated with ASD (P=0.039) and schizophrenia (P=0.008), common variants in LRP1 show gene-based association in schizophrenia (P=6.6E-07) and in a meta-analysis across seven psychiatric disorders (P=1.2E-05), and LRP1 exhibits an increased burden of ultra-rare pathogenic variants in a cohort of ASD probands from the ARRA Autism Sequencing Collaboration compared to controls (35 variants in 1778 ASD probands vs. 64 variants in 7875 controls; P-value of 1.2E-05).

Krishnan Probability Score

Score 0.4087301651779

Ranking 22904/25841 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.
Original Source
ExAC Score

Score 1

Ranking 10/18225 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
Original Source
Iossifov Probability Score

Score 1

Ranking 2/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.94878986337402

Ranking 17827/18665 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).
Original Source
Zhang D Score

Score 0.20981813711778

Ranking 4119/20870 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.
Original Source
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