Kidney Week

Abstract: SA-PO579

PRDM15 Mutations Cause Steroid-Resistant Nephrotic Syndrome with Microcephaly, Polydactyly, and Heart Defects

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

• Ashraf, Shazia, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shazia Ashraf,

• Schanze, Denny, Institute of Human Genetics, Magdeburg, Germany

Denny Schanze,

• van der Ven, Amelie, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States

Amelie van der Ven,

• Shi, Shasha, INSERM, Grenoble, France

Shasha Shi,

• Lovric, Svjetlana, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States

Svjetlana Lovric,

• Soliman, Neveen, Cairo University, Cairo, Egypt

Neveen Soliman,

• Jairajpuri, Mohamad Aman, Jamia Millia Islamia University, New-Delhi, India

Mohamad Aman Jairajpuri,

• Kadlec, Jan, INSERM, Grenoble, France

Jan Kadlec,

• Zenker, Martin, Institute of Human Genetics, Magdeburg, Germany

Martin Zenker,

• Hildebrandt, Friedhelm, Boston Childrens Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease in children and young adults. First insights into the pathogenesis of SRNS came from identification of >50 single-gene causes. PRDM proteins contain SET domain and multiple zinc fingers domains, and are involved in transcriptional regulation.

Methods

We performed whole exome sequencing (WES) to identify novel monogenic causes of SRNS in >1,000 individuals with SRNS.

Results

We identified 3 different recessive mutations in PRDM15 (PR domain containing 15) (p.M483K, E519K and C1173Y) in 6 unrelated families. Interestingly, 4 affected individuals with the C1173Y mutated allele exhibited SRNS (childhood-onset) with microcephaly, polydactyly, and heart defects, while the 2 mutations in the SET domain of PRDM15 only caused isolated SRNS. C1173 is a critical “cysteine” residue at the “knuckle” of the Cys-x-x-Cys sequence necessary to complex the zinc ion. We tested the stability of wild type (WT) protein versus two mutations (M483K and E519K) in the SET domain of PRDM15, using thermal stability assay by tryptophan absorption. We demonstrate that the M483K mutant was significantly less stable than WT, while the E519K mutant was insoluble. Further, we show that stable knockdown of PRDM15 results in decreased cell migration and severe proliferation defects in cultured human podocytes. WT, but not 3 mutant, constructs rescue the migration defects in podocytes, confirming deleteriousness of the mutations that we identified in SRNS patients. By immunofluorescence studies, we find that PRDM15 colocalizes with fibrillarin at nucleoli of human podocytes.

Conclusion

We have identified PRDM15 mutations as a novel cause of childhood-onset SRNS with microcephaly, polydactyly and heart defects. Our findings may implicate a defect in a transcriptional program as a new cause of SRNS.

Funding

• Other NIH Support