DZIP1L – Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by early-onset cystic dilation of renal collecting ducts, enlarged echogenic kidneys, and hypertension. While PKHD1 is the major locus, DZIP1L encodes a basal body protein implicated in rare ARPKD cases and functions in primary cilia maintenance. Genetic screening panels for polycystic kidney diseases are increasingly including DZIP1L to improve diagnostic yield (PMID:38097330).

To date, four unrelated children from three consanguineous families have been reported with ARPKD due to homozygous DZIP1L variants (PMID:35211789). All affected individuals presented with cystic dysplasia and systemic hypertension without clinically significant liver fibrosis. Variants described include two novel missense changes affecting conserved N-terminal cysteine residues.

Segregation analysis in three multiplex consanguineous pedigrees demonstrated recessive inheritance with homozygous variants in affected siblings and heterozygous carrier parents; no additional distant affected relatives were reported (PMID:35211789). This pattern is consistent with loss of function via biallelic disruption.

The variant spectrum includes c.193T>C (p.Cys65Arg) and c.216G>T (p.Cys72Trp), both altering invariant cysteines in the N-terminal domain crucial for basal body localization. No recurrent or founder alleles have been documented outside these pedigrees.

Functional assays demonstrated mislocalization of the p.Cys72Trp mutant DZIP1L protein in cultured cells, supporting a loss-of-function mechanism and phenocopying ciliary defects seen in PKHD1 models (PMID:35211789).

Integration of genetic and functional data supports a Moderate level of evidence for DZIP1L in ARPKD. Inclusion of DZIP1L in clinical gene panels facilitates molecular diagnosis in atypical or PKHD1-negative cases, guiding management and genetic counseling.

References

• Pediatric Nephrology (Berlin, Germany) • 2022 • Detection of DZIP1L mutations by whole-exome sequencing in consanguineous families with polycystic kidney disease. PMID:35211789
• Advances in Kidney Disease and Health • 2023 • Genetic Spectrum of Polycystic Kidney and Liver Diseases and the Resulting Phenotypes. PMID:38097330

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