16p11.2 transcription factor <i>MAZ</i> is a dosage-sensitive regulator of genitourinary development.

Abstract

Genitourinary (GU) birth defects are among the most common yet least studied congenital malformations. Congenital anomalies of the kidney and urinary tract (CAKUTs) have high morbidity and mortality rates and account for ∼30% of structural birth defects. Copy number variation (CNV) mapping revealed that 16p11.2 is a hotspot for GU development. The only gene covered collectively by all of the mapped GU-patient CNVs was MYC-associated zinc finger transcription factor (<i>MAZ</i>), and <i>MAZ</i> CNV frequency is enriched in nonsyndromic GU-abnormal patients. Knockdown of <i>MAZ</i> in HEK293 cells results in differential expression of several WNT morphogens required for normal GU development, including Wnt11 and Wnt4. <i>MAZ</i> knockdown also prevents efficient transition into S phase, affects transcription of cell-cycle regulators, and abrogates growth of human embryonic kidney cells. Murine <i>Maz</i> is ubiquitously expressed, and a CRISPR-Cas9 mouse model of <i>Maz</i> deletion results in perinatal lethality with survival rates dependent on <i>Maz</i> copy number. Homozygous loss of <i>Maz</i> results in high penetrance of CAKUTs, and <i>Maz</i> is haploinsufficient for normal bladder development. <i>MAZ</i>, once thought to be a simple housekeeping gene, encodes a dosage-sensitive transcription factor that regulates urogenital development and contributes to both nonsyndromic congenital malformations of the GU tract as well as the 16p11.2 phenotype.