{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T03:33:41Z","timestamp":1785900821243,"version":"3.56.0"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"health labor sciences research grant","award":["H24-nanchi-ippan-041"],"award-info":[{"award-number":["H24-nanchi-ippan-041"]}]},{"name":"health labor sciences research grant","award":["H29-nanchi-ippan-039"],"award-info":[{"award-number":["H29-nanchi-ippan-039"]}]},{"DOI":"10.13039\/501100001691","name":"japan society for the promotion of science","doi-asserted-by":"crossref","award":["JP15K09261"],"award-info":[{"award-number":["JP15K09261"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"japan society for the promotion of science","doi-asserted-by":"crossref","award":["18K08243"],"award-info":[{"award-number":["18K08243"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Exp Nephrol"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the <jats:italic>PKHD1<\/jats:italic> 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p><jats:italic>PKHD1<\/jats:italic> pathogenic variants were identified in 32 patients (0\u201346\u00a0years). 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\u20132 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\u2009&gt;\u2009T (p.Gln905Ter) and c.6808\u2009+\u20091G\u2009&gt;\u2009A expressed a transcript that skipped exon 25 (123\u00a0bp) and exon 41 (126\u00a0bp), 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.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>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.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s10157-021-02135-3","type":"journal-article","created":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T13:02:28Z","timestamp":1631970148000},"page":"140-153","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Clinical features of autosomal recessive polycystic kidney disease in the Japanese population and analysis of splicing in PKHD1 gene for determination of phenotypes"],"prefix":"10.1007","volume":"26","author":[{"given":"Shinya","family":"Ishiko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9676-865X","authenticated-orcid":false,"given":"Naoya","family":"Morisada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadayuki","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Aoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rini","family":"Rossanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana","family":"Sakakibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"China","family":"Nagano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Horinouchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Yamamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Ninchoji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kaito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riku","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Shima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masafumi","family":"Matsuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumoto","family":"Iijima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kandai","family":"Nozu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"issue":"3","key":"2135_CR1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/ng833","volume":"30","author":"CJ Ward","year":"2002","unstructured":"Ward CJ, Hogan MC, Rossetti S, Walker D, Sneddon T, Wang X, et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet. 2002;30(3):259\u201369. https:\/\/doi.org\/10.1038\/ng833.","journal-title":"Nat Genet"},{"issue":"5","key":"2135_CR2","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1086\/340448","volume":"70","author":"LF Onuchic","year":"2002","unstructured":"Onuchic LF, Furu L, Nagasawa Y, Hou X, Eggermann T, Ren Z, et al. PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet. 2002;70(5):1305\u201317. https:\/\/doi.org\/10.1086\/340448.","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2135_CR3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1083\/jcb.200910096","volume":"188","author":"JA Follit","year":"2010","unstructured":"Follit JA, Li L, Vucica Y, Pazour GJ. The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol. 2010;188(1):21\u20138. https:\/\/doi.org\/10.1083\/jcb.200910096.","journal-title":"J Cell Biol"},{"issue":"7","key":"2135_CR4","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/ng.3871","volume":"49","author":"H Lu","year":"2017","unstructured":"Lu H, Galeano MCR, Ott E, Kaeslin G, Kausalya PJ, Kramer C, et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat Genet. 2017;49(7):1025\u201334. https:\/\/doi.org\/10.1038\/ng.3871.","journal-title":"Nat Genet"},{"key":"2135_CR5","volume-title":"Gene Reviews","author":"WE Sweeney","year":"2001","unstructured":"Sweeney WE, Avner ED, et al. Polycystic Kidney Disease, Autosomal Recessive. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews. Seattle: University of Washington; 2001."},{"issue":"10","key":"2135_CR6","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1007\/s00467-013-2634-1","volume":"29","author":"R Buscher","year":"2014","unstructured":"Buscher R, Buscher AK, Weber S, Mohr J, Hegen B, Vester U, et al. Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes. Pediatr Nephrol. 2014;29(10):1915\u201325. https:\/\/doi.org\/10.1007\/s00467-013-2634-1.","journal-title":"Pediatr Nephrol"},{"issue":"1","key":"2135_CR7","doi-asserted-by":"publisher","first-page":"7919","DOI":"10.1038\/s41598-019-43488-w","volume":"9","author":"K Burgmaier","year":"2019","unstructured":"Burgmaier K, Kilian S, Bammens B, Benzing T, Billing H, Buscher A, et al. Clinical courses and complications of young adults with autosomal recessive polycystic kidney disease (ARPKD). Sci Rep. 2019;9(1):7919. https:\/\/doi.org\/10.1038\/s41598-019-43488-w.","journal-title":"Sci Rep"},{"issue":"1","key":"2135_CR8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/01.md.0000200165.90373.9a","volume":"85","author":"M Adeva","year":"2006","unstructured":"Adeva M, El-Youssef M, Rossetti S, Kamath PS, Kubly V, Consugar MB, et al. Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore). 2006;85(1):1\u201321. https:\/\/doi.org\/10.1097\/01.md.0000200165.90373.9a.","journal-title":"Medicine (Baltimore)"},{"issue":"3","key":"2135_CR9","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1111\/j.1523-1755.2005.00148.x","volume":"67","author":"C Bergmann","year":"2005","unstructured":"Bergmann C, Senderek J, Windelen E, Kupper F, Middeldorf I, Schneider F, et al. Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Kidney Int. 2005;67(3):829\u201348. https:\/\/doi.org\/10.1111\/j.1523-1755.2005.00148.x.","journal-title":"Kidney Int"},{"issue":"5 Pt 1","key":"2135_CR10","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1542\/peds.111.5.1072","volume":"111","author":"LM Guay-Woodford","year":"2003","unstructured":"Guay-Woodford LM, Desmond RA. Autosomal recessive polycystic kidney disease: the clinical experience in North America. Pediatrics. 2003;111(5 Pt 1):1072\u201380. https:\/\/doi.org\/10.1542\/peds.111.5.1072.","journal-title":"Pediatrics"},{"issue":"10","key":"2135_CR11","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1007\/s00109-014-1185-7","volume":"92","author":"R Boddu","year":"2014","unstructured":"Boddu R, Yang C, O\u2019Connor AK, Hendrickson RC, Boone B, Cui X, et al. Intragenic motifs regulate the transcriptional complexity of Pkhd1\/PKHD1. J Mol Med (Berl). 2014;92(10):1045\u201356. https:\/\/doi.org\/10.1007\/s00109-014-1185-7.","journal-title":"J Mol Med (Berl)"},{"issue":"4","key":"2135_CR12","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1007\/s10157-018-1534-x","volume":"22","author":"C Nagano","year":"2018","unstructured":"Nagano C, Nozu K, Morisada N, Yazawa M, Ichikawa D, Numasawa K, et al. Detection of copy number variations by pair analysis using next-generation sequencing data in inherited kidney diseases. Clin Exp Nephrol. 2018;22(4):881\u20138. https:\/\/doi.org\/10.1007\/s10157-018-1534-x.","journal-title":"Clin Exp Nephrol"},{"issue":"4","key":"2135_CR13","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1007\/s00439-009-0697-7","volume":"126","author":"K Nozu","year":"2009","unstructured":"Nozu K, Iijima K, Kawai K, Nozu Y, Nishida A, Takeshima Y, et al. In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation. Hum Genet. 2009;126(4):533\u20138. https:\/\/doi.org\/10.1007\/s00439-009-0697-7.","journal-title":"Hum Genet"},{"issue":"1","key":"2135_CR14","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1097\/01.asn.0000039578.55705.6e","volume":"14","author":"C Bergmann","year":"2003","unstructured":"Bergmann C, Senderek J, Sedlacek B, Pegiazoglou I, Puglia P, Eggermann T, et al. Spectrum of mutations in the gene for autosomal recessive polycystic kidney disease (ARPKD\/PKHD1). J Am Soc Nephrol. 2003;14(1):76\u201389. https:\/\/doi.org\/10.1097\/01.asn.0000039578.55705.6e.","journal-title":"J Am Soc Nephrol"},{"issue":"2","key":"2135_CR15","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1007\/s00247-008-1064-x","volume":"39","author":"B Turkbey","year":"2009","unstructured":"Turkbey B, Ocak I, Daryanani K, Font-Montgomery E, Lukose L, Bryant J, et al. Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD\/CHF). Pediatr Radiol. 2009;39(2):100\u201311. https:\/\/doi.org\/10.1007\/s00247-008-1064-x.","journal-title":"Pediatr Radiol"},{"issue":"3","key":"2135_CR16","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1515\/jpem.2005.18.3.315","volume":"18","author":"GS Jeha","year":"2005","unstructured":"Jeha GS, Tatevian N, Heptulla RA. Congenital hypothyroidism in association with Caroli\u2019s disease and autosomal recessive polycystic kidney disease: patient report. J Pediatr Endocrinol Metab. 2005;18(3):315\u20138. https:\/\/doi.org\/10.1515\/jpem.2005.18.3.315.","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"3","key":"2135_CR17","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1297\/cpe.24.107","volume":"24","author":"K Nagasaki","year":"2015","unstructured":"Mass Screening Committee, Japanese Society for Pediatric Endocrinology, Japanese Society for Mass Screening, Nagasaki K, Minamitani K, Anzo M, et al. Guidelines for Mass Screening of Congenital Hypothyroidism (2014 revision). Clin Pediatr Endocrinol. 2015;24(3):107\u201333. https:\/\/doi.org\/10.1297\/cpe.24.107.","journal-title":"Clin Pediatr Endocrinol"},{"issue":"6","key":"2135_CR18","doi-asserted-by":"publisher","first-page":"R297","DOI":"10.1530\/EJE-18-0383","volume":"179","author":"C Peters","year":"2018","unstructured":"Peters C, van Trotsenburg ASP, Schoenmakers N. Diagnosis of endocrine disease: congenital hypothyroidism: update and perspectives. Eur J Endocrinol. 2018;179(6):R297\u2013317. https:\/\/doi.org\/10.1530\/EJE-18-0383.","journal-title":"Eur J Endocrinol"},{"issue":"3","key":"2135_CR19","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/BF02896572","volume":"55","author":"A Martin","year":"1988","unstructured":"Martin A, Hedinger C, Haberlin-Jakob M, Walt H. Structure and motility of primary cilia in the follicular epithelium of the human thyroid. Virchows Arch B Cell Pathol Incl Mol Pathol. 1988;55(3):159\u201366. https:\/\/doi.org\/10.1007\/BF02896572.","journal-title":"Virchows Arch B Cell Pathol Incl Mol Pathol"},{"issue":"4","key":"2135_CR20","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1089\/thy.2018.0401","volume":"29","author":"JM Fernandez-Santos","year":"2019","unstructured":"Fernandez-Santos JM, Utrilla JC, Vazquez-Roman V, Villar-Rodriguez JL, Gutierrez-Aviles L, Martin-Lacave I. Primary Cilium in the human thyrocyte: changes in frequency and length in relation to the functional pathology of the thyroid gland. Thyroid. 2019;29(4):595\u2013606. https:\/\/doi.org\/10.1089\/thy.2018.0401.","journal-title":"Thyroid"},{"issue":"10","key":"2135_CR21","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.2215\/CJN.00920114","volume":"9","author":"V Frank","year":"2014","unstructured":"Frank V, Zerres K, Bergmann C. Transcriptional complexity in autosomal recessive polycystic kidney disease. Clin J Am Soc Nephrol. 2014;9(10):1729\u201336. https:\/\/doi.org\/10.2215\/CJN.00920114.","journal-title":"Clin J Am Soc Nephrol"},{"issue":"10","key":"2135_CR22","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1007\/s00467-018-3992-5","volume":"33","author":"T Szabo","year":"2018","unstructured":"Szabo T, Orosz P, Balogh E, Javorszky E, Mattyus I, Bereczki C, et al. Comprehensive genetic testing in children with a clinical diagnosis of ARPKD identifies phenocopies. Pediatr Nephrol. 2018;33(10):1713\u201321. https:\/\/doi.org\/10.1007\/s00467-018-3992-5.","journal-title":"Pediatr Nephrol"}],"container-title":["Clinical and Experimental Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10157-021-02135-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10157-021-02135-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10157-021-02135-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T17:05:23Z","timestamp":1642611923000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10157-021-02135-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":22,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["2135"],"URL":"https:\/\/doi.org\/10.1007\/s10157-021-02135-3","relation":{},"ISSN":["1342-1751","1437-7799"],"issn-type":[{"value":"1342-1751","type":"print"},{"value":"1437-7799","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]},"assertion":[{"value":"18 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"K.I. has received grant support from Daiichi Sankyo Co., Ltd. and Zenyaku Kogyo Co., Ltd.\u00a0M. M discloses being employed by Kobe Gakuin University, which received funding from KNC Laboratories Inc. (Kobe, Japan). The author further discloses being a scientific adviser for Daiichi-Sankyo Co. (Tokyo, Japan) and JCR Pharma Co. (Ashiya, Japan).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}