Kidney Week

Abstract: TH-PO703

ZMYM2 Mutations Cause Congenital Anomalies of the Kidneys and Urinary Tract (CAKUT) with Syndromic Features

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

• Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States

Dervla M. Connaughton,

• Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States

Nina Mann,

• Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States

Makiko Nakayama,

• Dai, Rufeng, Boston Children's Hospital, Boston, Massachusetts, United States

Rufeng Dai,

• Kolvenbach, Caroline M., Harvard Medical School, Boston, Massachusetts, United States

Caroline M. Kolvenbach,

• Kause, Franziska, Boston Children's Hospital, Boston, Massachusetts, United States

Franziska Kause,

• Ahram, Dina, Columbia University Medical Center, New York, New York, United States

Dina Ahram,

• Milo Rasouly, Hila, Columbia University, New York, New York, United States

Hila Milo Rasouly,

• Sanna-Cherchi, Simone, Columbia University, New York, New York, United States

Simone Sanna-Cherchi,

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

Shirlee Shril,

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

Friedhelm Hildebrandt,

Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause (45%) of chronic kidney disease in the first three decades of life. CAKUT can present as an isolated renal condition or as part of a clinical syndrome. First insights into the pathogenesis of CAKUT came from identification of ~40 single-gene causes of isolated CAKUT and ~179 single-gene causes of syndromic CAKUT.

Methods

We performed whole exome sequencing (WES) to identify novel monogenic causes in a worldwide cohort of 600 individuals with CAKUT.

Results

We identified 13 different dominant heterozygous mutations in ZMYM2 (MYM-type zinc fingers type 2) in 15 unrelated families; p.Val61del, p.Glu126Ala, p.G257fs p.Ile387Val, p.Gln398*, p.Cys536Leufs*13, p.Arg540ins*, p.Lys649Arg, p.Tyr763His, p.Gly775Glu, p.Asp997del, p.Pro1002Ser, p.Glu1031Lys. ZMYM2, a transcriptional regulator, contains 10 tandem zinc fingers called myeloproliferative and mental retardation (MYM)-type zinc fingers. ZMYM2 is expressed in the urothelial cells and renal tubules in human cells and in the bladder and genital tubercle of the developing mouse. The encoded protein acts as a transcriptional co-repressor as part of the BHC histone deacetylase complex and through interaction with SUMO-2. Affected individuals exhibited a broad spectrum of CAKUT phenotypes. In addition, there were genito-urinary tract pathologies including imperforate hymen and cryptorchidism. Interestingly, patients carrying missense alleles had an isolated CAKUT phenotype, whereas patients carrying truncating alleles exhibited syndromic features such as facial dysmorphsim, developmental delay, hypotonia, and autism spectrum disorder.

Conclusion

We here discovered ZMYM2 mutations as a novel cause of autosomal dominant CAKUT. Furthermore, we found evidence of an allelic genotype-phenotype correlation, in which null mutations in ZMYM2 (e.g., protein truncating) cause syndromic CAKUT phenotypes, whereas hypomorphic mutations (e.g., missense) cause isolated CAKUT phenotypes.

Funding

• Other NIH Support