Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes

Shinya Ishiko,Masafumi Matsuo,Takeshi Ninchoji,Tomohiko Yamamura,Kazumoto Iijima,Yuya Aoto,Koichi Nakanishi,Riku Hamada,Tomoko Horinouchi,Yuko Shima,Naoya Morisada,Eri Okada,China Nagano,Sadayuki Nagai,Hiroshi Kaito,Kandai Nozu,Nana Sakakibara,Rini Rossanti,Atsushi Kondo

doi:10.1007/s10157-021-02135-3

Abstract

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. The clinical spectrum is often more variable than previously considered. We aimed to analyze the clinical features of genetically diagnosed ARPKD in the Japanese population.MethodsWe conducted a genetic analysis of patients with clinically diagnosed or suspected ARPKD in Japan. Moreover, we performed a minigene assay to elucidate the mechanisms that could affect phenotypes.ResultsPKHD1 pathogenic variants were identified in 32 patients (0–46 years). Approximately one-third of the patients showed prenatal anomalies, and five patients died within one year after birth. Other manifestations were detected as follows: chronic kidney disease stages 1–2 in 15/26 (57.7%), Caroli disease in 9/32 (28.1%), hepatic fibrosis in 7/32 (21.9%), systemic hypertension in 13/27 (48.1%), and congenital hypothyroidism in 3 patients. There have been reported that truncating mutations in both alleles led to severe phenotypes with perinatal demise. However, one patient without a missense mutation survived the neonatal period. In the minigene assay, c.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. Missense mutations in cases of neonatal demise did not show splicing abnormalities.ConclusionClinical manifestations ranged from cases of neonatal demise to those diagnosed in adulthood. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival.

Highlights

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited cilia-related disorder characterized by the association of bilateral renal cystic disease and congenital hepatic fibrosis
The polycystic kidney and hepatic disease 1 (PKHD1) gene has been identified as the causative gene for ARPKD [1, 2], with 590 types of pathogenic mutation reported in The Human Gene Mutation Database to date
Mutations in DAZ interacting protein 1-like (DZIP1L) have been reported in patients with ARPKD, suggesting that ARPKD is not a homogeneous disorder and DZIP1L may be involved in its pathogenesis [4], whether there is a causative relationship between DZIP1L and ARPKD requires further investigation [5]

Summary

Introduction

Autosomal recessive polycystic kidney disease (ARPKD) is an inherited cilia-related disorder characterized by the association of bilateral renal cystic disease and congenital hepatic fibrosis. The polycystic kidney and hepatic disease 1 (PKHD1) gene has been identified as the causative gene for ARPKD [1, 2], with 590 types of pathogenic mutation reported in The Human Gene Mutation Database to date (http://www.hgmd.cf.ac.uk, HGMD). Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 gene. C.2713C > T (p.Gln905Ter) and c.6808 + 1G > A expressed a transcript that skipped exon 25 (123 bp) and exon 41 (126 bp), resulting in an in-frame mutation, which might have contributed to the milder phenotype. The minigene assay results indicate the importance of functional analysis, and call into question the fundamental belief that at least one non-truncating mutation is necessary for perinatal survival

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