Kidney Week

Abstract: SA-PO767

Discovery of a Novel Candidate Gene Implicated in X-Linked Polycystic Kidney Disease

Session Information

• Genetic Diseases: Cystic - Genetic Analysis and Extrarenal Manifestations
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Mori, Takayasu, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Takayasu Mori,

• Fujimaru, Takuya, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Takuya Fujimaru,

• Liu, Chunyu, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, Shanghai, China

Chunyu Liu,

• Patterson, Karynne, University of Washington, Seattle, Washington, United States

Karynne Patterson,

• Yamamoto, Kohei, Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

Kohei Yamamoto,

• Suzuki, Takefumi, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Takefumi Suzuki,

• Chiga, Motoko, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Motoko Chiga,

• Mandai, Shintaro, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Shintaro Mandai,

• Ando, Fumiaki, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Fumiaki Ando,

• Mori, Yutaro, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Yutaro Mori,

• Susa, Koichiro, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Koichiro Susa,

• Tan, Yue-Qiu, Institute of Reproductive and Stem Cell Engineering, NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, School of Basic Medical Science, Central South University, Changsha, Changsha , China

Yue-Qiu Tan,

• Zhang, Feng, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, Shanghai, China

Feng Zhang,

• Uchida, Shinichi, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Shinichi Uchida,

• Sohara, Eisei, Department of Nephrology, Tokyo Medical and Dental Sciences, Tokyo, Japan, Bunkyo-ku, Tokyo, Japan

Eisei Sohara,

Group or Team Name

• University of Washington Center for Rare Disease Research.

Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by typical imaging findings and a family history and ~90% of cases have a genetic explanation. In contrast, the underlying genetic basis of adult-onset sporadic cystic kidney disease remains incompletely elucidated, with ~30% of patients in our cohort remaining unexplained by variants in established cyst-related genes, leading to inconclusive diagnoses. These individuals were presumed to harbor potentially unreported mutations in novel candidate genes associated with PKD.

Methods

An NGS panel screening was conducted to analyze 69 known genes associated with renal cysts in adult patients with no familial history of the condition. Whole genome sequencing was performed on 47 unrelated individuals who did not exhibit any pathogenic candidate variants, aiming to identify novel genes implicated in renal cyst formation.

Results

Candidate gene A, located on the X chromosome, exhibited missense variants found in three male patients aged 74 (PT570), 80 (PT698), and 58 (PT1216) years, respectively. These patients demonstrated renal function impairment with estimated glomerular filtration rates (eGFR) of 53.5, 21.8, and 20.2 ml/min/1.73m², respectively. Hypertension was a shared characteristic among all patients, while no complications associated with hepatic cysts were observed. The protein product of gene A was found to be expressed in the primary cilia of human renal tubules. Kidneys from 12-month-old male knockout mice lacking gene A exhibited vacuolation of tubular cells and tubular dilation, providing evidence that gene A is a novel causative gene involved in cyst formation.

Conclusion

Gene A is a newly discovered gene associated with PKD, demonstrating X-linked inheritance, which is uncommon in inherited cases of PKD. Further accumulation of cases is warranted for a more comprehensive understanding.

Funding

• Government Support – Non-U.S.