Polycystic Kidney Disease 5

A number sign (#) is used with this entry because of evidence that polycystic kidney disease-5 (PKD5) is caused by homozygous mutation in the DZIP1L gene (617570) on chromosome 3q22.

Description

PKD5, a form of autosomal recessive polycystic kidney disease (ARPKD), is characterized by early childhood onset of progressive renal dysfunction associated with enlarged hyperechogenic kidneys that often results in end-stage renal disease in the second or third decade of life. Arterial hypertension is apparent in early childhood (summary by Lu et al., 2017).

For a discussion of genetic heterogeneity of polycystic kidney disease, see PKD1 (173900).

Clinical Features

Lu et al. (2017) reported 7 patients from 4 unrelated consanguineous families with PKD5. The patients had childhood onset of progressive renal dysfunction associated with arterial hypertension in the first years of life. Renal ultrasound showed bilaterally enlarged, hyperechogenic kidneys with poor or even absent corticomedullary differentiation and multiple tiny cysts. At least 1 patient had punctate calcifications on imaging. Four patients had progressive disease, resulting in end-stage renal disease in the teenage years and necessitating renal transplant in the teenage years or as young adults. However, 3 patients had essentially normal renal function at ages 9, 13, and 15, respectively; Lu et al. (2017) suggested that these individuals may develop end-stage renal disease later in life. None of the patients had clinical evidence of hepatic fibrosis.

Inheritance

The transmission pattern of PKD5 in the family reported by Lu et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 7 patients from 4 unrelated consanguineous families with PKD5, Lu et al. (2017) identified homozygous missense or truncating mutations in the DZIP1L gene (617570.0001-617570.0004). Mutations in the first 2 families, which were found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Mutations in the second 2 families were found by direct sequencing of the DZIP1L gene in 218 unrelated subjects with suspected ARPKD or next-generation sequencing of a targeted gene panel in 1,330 individuals with a similar phenotype. Fibroblasts derived from 1 of the patients with a truncating mutation showed no obvious differences in the percentage of ciliated cells, cilia morphology, or localization of several markers of cilia and basal bodies compared to controls. However, the cilia showed decreased accumulation of PKD1 (601313) and PKD2 (173910) along the ciliary membrane compared to controls. These findings suggested that, in the absence of correct DZIP1L function, the ciliary-membrane distribution of PKD1 and PKD2 is compromised, possibly reflecting a defect in the barrier function of the transition zone.

Animal Model

In a recessive N-ethyl-N-nitrosourea mutagenesis screen, Lu et al. (2017) identified the mouse 'warpy' (wpy) mutant and found that wpy was a nonsense mutation (Q375X) in a region of the Dzip1l gene encoding the coiled-coil domains. Dzip1l wpy/wpy mutants showed widespread dysmorphologies, including highly penetrant polydactyly of all 4 limbs, gross eye abnormalities, and craniofacial defects, including cleft lip/palate. Some of the mouse mutants showed embryonic death. On an outbred genetic background, Dzip1l wpy/wpy mice were obtained at the expected mendelian frequency, although they failed to thrive and were sacrificed by postnatal day 21. These Dzip1l wpy/wpy mice showed early-onset progressive cystic kidney disease, with cysts arising from collecting ducts and proximal tubules. There were also subtle signs of hepatic abnormalities and ductal plate malformations with an excess of bile ducts, but no frank fibrosis. Dzip1l wpy/wpy fibroblasts showed evidence of a defect in Shh (600725) signaling and abnormal ciliary membrane distribution of Pc1 (PKD1; 601313) and Pc2 (PKD2; 173910), possibly reflecting a defect in the barrier function of the transition zone. Inactivation of zebrafish dzip1l also caused phenotypes consistent with ciliary dysfunction.