Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes
| Autor: | China Nagano, Koichi Nakanishi, Tomohiko Yamamura, Takeshi Ninchoji, Hiroshi Kaito, Rini Rossanti, Masafumi Matsuo, Yuko Shima, Sadayuki Nagai, Kazumoto Iijima, Riku Hamada, Yuya Aoto, Naoya Morisada, Nana Sakakibara, Shinya Ishiko, Eri Okada, Tomoko Horinouchi, Atsushi Kondo, Kandai Nozu |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Adult
medicine.medical_specialty Caroli disease Physiology Receptors Cell Surface PKHD1 Gastroenterology Exon Japan Pregnancy Physiology (medical) Internal medicine medicine Humans Missense mutation Genetic Testing Allele Minigene assay Autosomal recessive polycystic kidney disease Polycystic Kidney Autosomal Recessive business.industry medicine.disease Autosomal Recessive Polycystic Kidney Disease Congenital hypothyroidism Phenotype Nephrology Mutation Female Original Article business Hepatic fibrosis Kidney disease Minigene |
| Zdroj: | Clinical and Experimental Nephrology |
| ISSN: | 1342-1751 |
| Popis: | Background Autosomal 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. Methods We 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. Results PKHD1 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. Conclusion Clinical 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. |
| Databáze: | OpenAIRE |
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