Kidney Week

Abstract: TH-PO702

Mutations in PIK3C2A Cause Syndromic Short Stature Associated with Eye, Skeletal, and Renal Involvement

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - I
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Schueler, Markus, University of Erlangen-Nuernberg, Erlangen, Germany

Markus Schueler,

• Chen, Anlu, Case Western Reserve Univ, Cleveland, Ohio, United States

Anlu Chen,

• Tiosano, Dov, Mayer Children`s Hospital, Haifa, Israel

Dov Tiosano,

• Baris, Hagit N., Rambam Health Care Campus, Haifa, Israel

Hagit N. Baris,

• Hitzert, Marrit, University Medical Center Groningen, Groningen, Netherlands

Marrit Hitzert,

• Mory, Adi, Rambam health care campus, Haifa, Israel

Adi Mory,

• Knaup, Karl, University of Erlangen-Nuremberg, Erlangen, Germany

Karl Knaup,

• Roepman, Ronald, Radboud University Medical Center, Nijmegen, Netherlands

Ronald Roepman,

• Pfundt, Rolph, RadboudUMC, Nijmegen, Netherlands

Rolph Pfundt,

• Aslanyan, Mariam, Radboud Institut for Molecular Life Science, Nijmegen, Netherlands

Mariam Aslanyan,

• Buchner, David A., Case Western Reserve University, Cleveland, Ohio, United States

David A. Buchner,

• Wiesener, Michael Sean, University Hospital Erlangen, Erlangen, Germany

Michael Sean Wiesener,

Background

PIK3C2A is a member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI). Class II PI3Ks has been attributed a wide-range of biological functions including, angiogenesis, cellular signaling, endosomal trafficking, exocytosis as well as ciliary formation and function. However, its function is still poorly understood. Identifying the genetic basis of Mendelian diseases provide insight into gene function, susceptibility to disease and can improve clinical care.

Methods

We performed whole exome sequencing in three independent consanguineous families to identify the underlying single-gene disease-causing mutation. We then obtained dermal fibroblasts from skin biopsies of the affected individual and healthy controls for molecular studies.

Results

We identified three homozygous protein-truncating mutations in the gene PIK3C2A in five children from independent consanguineous families. The affected individuals show a considerable overlapping phenotype including cataract, skeletal abnormalities, hearing loss and renal involvement among other features. Molecular data of patient-derived fibroblasts were consistent with loss of PIK3C2A function as evidenced by the lack of PIK3C2A protein. In addition we demonstrate that the PIK3C2A deficiency caused impaired cilia formation, decreased levels of PI in primary cilia, and altered the phosphorylation status of Akt, GSK3beta as well as the expression level of AXIN2.

Conclusion

We demonstrate that loss-of-function mutations in PIK3C2A resulting in a novel syndrome consisting of short stature, cataracts, hearing loss, skeletal abnormalities and renal involvement. This discovery, together with studies of other disorders of PI metabolism, will enable future studies to discover the pathophysiological mechanism basis of this syndrome to better understand the role of PIK3C2A.