Kidney Week

Abstract: SA-PO572

OXGR1 Mutations Present a Novel Cause of Nephrolithiasis

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States

Amar J. Majmundar,

• Daga, Ankana, Boston Children's Hospital, Boston, Massachusetts, United States

Ankana Daga,

• Braun, Daniela A., Boston Children's Hospital, Boston, Massachusetts, United States

Daniela A. Braun,

• Gee, Heon Yung, Yonsei University College of Medicine, Boston, Korea (the Republic of)

Heon Yung Gee,

• Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States

Shirlee Shril,

• Halbritter, Jan, University Clinic Leipzig, Leipzig, Germany

Jan Halbritter,

• Mane, Shrikant M., Yale Center For Mendelian Genomics, New Haven, Connecticut, United States

Shrikant M. Mane,

• Sayer, John Andrew, Newcastle University, Newcastle, United Kingdom

John Andrew Sayer,

• Fathy, Hanan, El Shatty Children’s Hospital, Alexandria, Egypt

Hanan Fathy,

• Baum, Michelle Amy, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle Amy Baum,

• Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant morbidity and cost including surgical intervention. There are >30 genes, for which causative mutations have been identified in 11% of adult and 17-20% of pediatric NL cases (Halbritter JASN 26:543, 2015; Braun cJASN 11:664, 2016). Identifying novel NL genes can reveal new pathogenic mechanisms.

Methods

We employed whole exome sequencing (WES) to identify novel genes in familial NL cases.

Results

By WES, we identified a heterozygous missense variant (c.371T>G, p.L124R) in the gene OXGR1 that segregated in 4 affected children and 1 affected mother from an Egyptian family with an autosomal dominant inheritance pattern of calcium oxalate containing NL and/or nephrocalcinosis (NC). OXGR1 encodes oxoglutarate receptor 1, a G-protein coupled receptor (GPCR) that is expressed in the distal nephron and promotes urinary alkalinization (Tokonami JCI 123:3166, 2013). The affected amino acid residue is conserved through vertebrate orthologues and in 72% of 300 human GPCR sequences. The predicted protein change showed strong SIFT and PolyPhen-2 scores. In the ExAC Exome Database, the allele is not found in the homozygous state and found once heterozygously in 60,632 individuals. Targeted sequencing of OXGR1 in 599 additional families with calcium oxalate containing NL and/or NC identified 3 additional alleles (c.649T>C, p.C217R; c.697A>C, p.S233R; c.860C>T, p.S287F) in 4 additional families (0.8% of cohort).

Conclusion

We identified OXGR1 mutations as novel monogenic cause of NL. As OXGR1 is implicated in urine alkalinization, further study of the disease mechanisms may provide insight into novel therapeutic options for NL.

Funding

• NIDDK Support