Exome Sequencing Reveals Cubilin Mutation as a Single-Gene Cause of Proteinuria

• Published in: Journal of the American Society of Nephrology Vol. 22; no. 10; pp. 1815 - 1820
• Main Authors: OVUNC, Bugsu, OTTO, Edgar A, YILMAZ, Engin, HILDEBRANDT, Friedhelm, VEGA-WARNER, Virginia, SAISAWAT, Pawaree, ASHRAF, Shazia, RAMASWAMI, Gokul, FATHY, Hanan M, SCHOEB, Dominik, CHERNIN, Gil, LYONS, Robert H
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society of Nephrology 01.10.2011
• Subjects: Biological and medical sciences; Brief Communications; Exome; Frameshift Mutation; Genes, Recessive; Homozygote; Humans; Medical sciences; Nephrology. Urinary tract diseases; Proteinuria - genetics; Receptors, Cell Surface - genetics; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Nephrology; Membrane protein; Urinary system disease; Gene; Nucleotide sequence; Cubilin; Genetics; Mutation; Sequencing; Urology; Proteinuria
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2011040337

In two siblings of consanguineous parents with intermittent nephrotic-range proteinuria, we identified a homozygous deleterious frameshift mutation in the gene CUBN, which encodes cubulin, using exome capture and massively parallel re-sequencing. The mutation segregated with affected members of this family and was absent from 92 healthy individuals, thereby identifying a recessive mutation in CUBN as the single-gene cause of proteinuria in this sibship. Cubulin mutations cause a hereditary form of megaloblastic anemia secondary to vitamin B(12) deficiency, and proteinuria occurs in 50% of cases since cubilin is coreceptor for both the intestinal vitamin B(12)-intrinsic factor complex and the tubular reabsorption of protein in the proximal tubule. In summary, we report successful use of exome capture and massively parallel re-sequencing to identify a rare, single-gene cause of nephropathy.