A number sign (#) is used with this entry because of evidence that polycystic kidney disease-7 (PKD7) is caused by heterozygous mutation in the ALG5 gene (604565) on chromosome 13q13.

Polycystic kidney disease-7 (PKD7) is an autosomal dominant nephropathy characterized by the development of small kidney cysts and renal interstitial fibrosis causing adult-onset progressive loss of kidney function leading to end-stage kidney disease after around 60 years of age. Many patients also demonstrate liver cysts and/or colonic diverticulosis (summary by Lemoine et al., 2022).

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

Lemoine et al. (2022) reported 19 patients from 5 unrelated families with adult-onset polycystic kidney disease (PCKD). Most of the patients were diagnosed after 30 years of age, although 1 was diagnosed at age 20. Some individuals, especially older ones, had chronic kidney disease or end-stage kidney disease associated with atrophic kidneys with multiple small kidney cysts. Renal histology from 1 patient who underwent nephrectomy showed multiple kidney cysts and extensive interstitial fibrosis. Decreased glomerular filtration rate (GFR) was also observed in the older patients. Other individuals, especially the younger ones, were identified incidentally or through family studies. These patients had normal-sized kidneys with few small kidney cysts. The authors noted that all individuals below 50 years of age had normal kidney function, all patients older than 60 years of age had chronic kidney disease, and 8 patients reached end-stage kidney disease between 62 and 91 years of age. About half of patients had high blood pressure, 7 had diverticulosis, and 6 had a few liver cysts.

Elhassan et al. (2024) reported 18 clinically affected patients out of 23 genetically-affected individuals from 2 distantly related Irish families (F350 and F200) with an adult-onset polycystic kidney disease-like phenotype and interstitial fibrosis. Affected persons developed slowly progressive chronic kidney disease caused by atypical cystic kidneys. Five of these patients reached end-stage kidney disease at a mean age of 73 years (range, 63-87 years). Eight patients had kidney and liver cysts (mean age, 72.7 years), 7 had only kidney cysts (mean age, 55.1 years), and 7 had no liver or kidney cysts (mean age, 50.2 years). Among the patients with advanced kidney disease, the displacement of normal kidney by cysts was less than expected, given the degree of kidney failure.

The transmission pattern of PKD7 in the families reported by Lemoine et al. (2022) was consistent with autosomal dominant inheritance.

In 19 patients from 5 unrelated families with PKD7, Lemoine et al. (2022) identified heterozygous mutations in the ALG5 gene (see, e.g., 604565.0001-604565.0004). There was 1 frameshift, 1 nonsense, 2 missense, and 1 splice site mutation. The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutations in families 2 and 3 were identified by targeted massively parallel sequencing of 1,213 individuals with kidney disease. The mutations in family 4 and in a singleton (family 5) were found by whole-genome sequencing of 3,520 probands with various renal diseases. The mutations segregated with the disorder in families 1, 2, 3, and 4. In vitro studies of CRISPR/Cas9-mediated biallelic and monoallelic frameshift mutations in the ALG5 gene expressed in renal cortical tubular epithelial (RCTE) cells showed abnormal accumulation of Man9GlcNAc2 lipid-linked oligosaccharide (LLO) precursors and their transfer onto proteins in human kidney cells. Further studies revealed that the lack of N-glycosylation resulted in abnormal maturation of the PKD1 (601313) protein that could be rescued by wildtype ALG5, but not by either of the missense variants. Lack of ALG5 also caused intracellular mislocalization of both PKD1 and PKD2 (173910), and evidence suggested that there was activation of the unfolded protein response.

In 2 distantly related Irish families (F350 and F200) with a late-onset autosomal dominant polycystic kidney disease-like phenotype and tubulointerstitial fibrosis, Elhassan et al. (2024) identified 23 individuals with a heterozygous R79W mutation in the ALG5 gene (604565.0005). Among these 23 individuals, 18 were clinically affected with a slowly progressive chronic kidney disease. The authors identified abnormal ALG5 distribution in the Golgi apparatus of renal tubular cells. Abnormal accumulation of uromodulin was noted in the endoplasmic reticulum, and decreased plasma and urinary uromodulin levels were also seen in affected persons, suggesting abnormal maturation and trafficking of uromodulin, resulting in structural and functional changes in the kidney.