Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Low density lipoprotein receptor-related protein 2

Mutations in LRP2 gene cause autosomal recessive Donnai-Barrow syndrome (DBS) and facio-oculoacoustico-renal syndrome (FOAR).

Protein Structure

Megalin, the product of the LRP2 gene, belongs to the LDL receptor family. I consists of a huge extracellular domain (4398 amino acids), a single transmembrane segment, and a short cytoplsmatic tail (209). The extracellular domain contains 36 cysteine-rich complement-type repeats in four clusters, 16 growth factor repeats separated by 8 YWTD spacers, and a single epidermal growth factor-like repeat. The intracellular domain contains 2 endocytic motifs (NPXY), 1 NPXY-like motif (NQNY), 1 SH3 domain, 1 PDZ domain, and phosphorylation sites.

Genetests:

Clinic Method Carrier testing
Turnaround 5 days
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 25 days
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25 days
Specimen type genomic DNA

Related Diseases:

Donnai-Barrow syndrome
LRP2

References:

1.

Nykjaer A et. al. (1999) An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.

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2.

Marinò M et. al. (1999) Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis.

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3.

Leheste JR et. al. (1999) Megalin knockout mice as an animal model of low molecular weight proteinuria.

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4.

Schmitz C et. al. (2002) Megalin deficiency offers protection from renal aminoglycoside accumulation.

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5.

Nykjaer A et. al. (2001) Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3).

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6.

Chassaing N et. al. (2003) Donnai-Barrow syndrome: four additional patients.

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7.

Nagai M et. al. (2003) The adaptor protein ARH escorts megalin to and through endosomes.

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8.

Tramontano A et. al. (2004) Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis.

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9.

Hammes A et. al. (2005) Role of endocytosis in cellular uptake of sex steroids.

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10.

Naccache SN et. al. (2006) Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.

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11.

Caruso-Neves C et. al. (2006) PKB and megalin determine the survival or death of renal proximal tubule cells.

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12.

Kantarci S et. al. (2007) Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.

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13.

Saito A et al. (2010) Molecular mechanisms of receptor-mediated endocytosis in the renal proximal tubular epithelium.

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14.

Raychowdhury R et. al. (1989) Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor.

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15.

Chatelet F et. al. (1986) Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli. II. Extrarenal distribution.

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16.

Kerjaschki D et. al. (1983) Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats.

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17.

Moestrup SK et. al. (1995) Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

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18.

Farquhar MG et. al. (1995) The Heymann nephritis antigenic complex: megalin (gp330) and RAP.

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19.

Chowdhary BP et. al. (1995) In situ hybridization mapping of a 500-kDa calcium-sensing protein gene (LRP2) to human chromosome region 2q31>q32.1 and porcine chromosome region 15q22>q24.

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20.

None (1995) The unfolding story of megalin (gp330): now recognized as a drug receptor.

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21.

Kounnas MZ et. al. (1995) Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin.

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22.

Saito A et. al. (1994) Complete cloning and sequencing of rat gp330/"megalin," a distinctive member of the low density lipoprotein receptor gene family.

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23.

Korenberg JR et. al. (1994) Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1).

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24.

Donnai D et. al. (1993) Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?

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25.

Hjälm G et. al. (1996) Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties.

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26.

Willnow TE et. al. (1996) Defective forebrain development in mice lacking gp330/megalin.

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27.

Devriendt K et. al. (1998) Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.

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Update: Sept. 26, 2018