Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes.
Autosomal recessive polycystic kidney disease
Congenital hypothyroidism
Hepatic fibrosis
Minigene assay
PKHD1
Journal
Clinical and experimental nephrology
ISSN: 1437-7799
Titre abrégé: Clin Exp Nephrol
Pays: Japan
ID NLM: 9709923
Informations de publication
Date de publication:
Feb 2022
Feb 2022
Historique:
received:
18
06
2021
accepted:
07
09
2021
pubmed:
19
9
2021
medline:
5
4
2022
entrez:
18
9
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 34536170
doi: 10.1007/s10157-021-02135-3
pii: 10.1007/s10157-021-02135-3
pmc: PMC8770369
doi:
Substances chimiques
PKHD1 protein, human
0
Receptors, Cell Surface
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
140-153Subventions
Organisme : health labor sciences research grant
ID : H24-nanchi-ippan-041
Organisme : health labor sciences research grant
ID : H29-nanchi-ippan-039
Organisme : japan society for the promotion of science
ID : JP15K09261
Organisme : japan society for the promotion of science
ID : 18K08243
Informations de copyright
© 2021. The Author(s).
Références
Nat Genet. 2002 Mar;30(3):259-69
pubmed: 11919560
J Mol Med (Berl). 2014 Oct;92(10):1045-56
pubmed: 24984783
Nat Genet. 2017 Jul;49(7):1025-1034
pubmed: 28530676
Pediatr Radiol. 2009 Feb;39(2):100-11
pubmed: 19089418
Clin J Am Soc Nephrol. 2014 Oct 7;9(10):1729-36
pubmed: 25104275
Medicine (Baltimore). 2006 Jan;85(1):1-21
pubmed: 16523049
Hum Genet. 2009 Oct;126(4):533-8
pubmed: 19513753
Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;55(3):159-66
pubmed: 2899923
Clin Pediatr Endocrinol. 2015 Jul;24(3):107-33
pubmed: 26594093
Pediatr Nephrol. 2018 Oct;33(10):1713-1721
pubmed: 29956005
Am J Hum Genet. 2002 May;70(5):1305-17
pubmed: 11898128
J Cell Biol. 2010 Jan 11;188(1):21-8
pubmed: 20048263
Kidney Int. 2005 Mar;67(3):829-48
pubmed: 15698423
J Am Soc Nephrol. 2003 Jan;14(1):76-89
pubmed: 12506140
Eur J Endocrinol. 2018 Sep 24;179(6):R297-R317
pubmed: 30324792
Clin Exp Nephrol. 2018 Aug;22(4):881-888
pubmed: 29372472
Pediatrics. 2003 May;111(5 Pt 1):1072-80
pubmed: 12728091
Sci Rep. 2019 May 28;9(1):7919
pubmed: 31138820
Thyroid. 2019 Apr;29(4):595-606
pubmed: 30767621
J Pediatr Endocrinol Metab. 2005 Mar;18(3):315-8
pubmed: 15813611
Pediatr Nephrol. 2014 Oct;29(10):1915-25
pubmed: 24114580