An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations

Abstract Meckel syndrome (MKS) is an inherited autosomal recessive hepatorenal fibrocystic syndrome, caused by mutations in TMEM67, characterized by occipital encephalocoele, renal cysts, hepatic fibrosis, and polydactyly. Here we describe an ovine model of MKS, with kidney and liver abnormalities,...

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Autores principales: C. Stayner, C. A. Poole, S. R. McGlashan, M. Pilanthananond, R. Brauning, D. Markie, B. Lett, L. Slobbe, A. Chae, A. C. Johnstone, C. G. Jensen, J. C. McEwan, K. Dittmer, K. Parker, A. Wiles, W. Blackburne, A. Leichter, M. Leask, A. Pinnapureddy, M. Jennings, J. A. Horsfield, R. J. Walker, M. R. Eccles
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spelling oai:doaj.org-article:edcafb5f13094ac2bfab71d2db069f8d2021-12-02T15:04:53ZAn ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations10.1038/s41598-017-01519-42045-2322https://doaj.org/article/edcafb5f13094ac2bfab71d2db069f8d2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01519-4https://doaj.org/toc/2045-2322Abstract Meckel syndrome (MKS) is an inherited autosomal recessive hepatorenal fibrocystic syndrome, caused by mutations in TMEM67, characterized by occipital encephalocoele, renal cysts, hepatic fibrosis, and polydactyly. Here we describe an ovine model of MKS, with kidney and liver abnormalities, without polydactyly or occipital encephalocoele. Homozygous missense p.(Ile681Asn; Ile687Ser) mutations identified in ovine TMEM67 were pathogenic in zebrafish phenotype rescue assays. Meckelin protein was expressed in affected and unaffected kidney epithelial cells by immunoblotting, and in primary cilia of lamb kidney cyst epithelial cells by immunofluorescence. In contrast to primary cilia of relatively consistent length and morphology in unaffected kidney cells, those of affected cyst-lining cells displayed a range of short and extremely long cilia, as well as abnormal morphologies, such as bulbous regions along the axoneme. Putative cilia fragments were also consistently located within the cyst luminal contents. The abnormal ciliary phenotype was further confirmed in cultured interstitial fibroblasts from affected kidneys. These primary cilia dysmorphologies and length control defects were significantly greater in affected cells compared to unaffected controls. In conclusion, we describe abnormalities involving primary cilia length and morphology in the first reported example of a large animal model of MKS, in which we have identified TMEM67 mutations.C. StaynerC. A. PooleS. R. McGlashanM. PilanthananondR. BrauningD. MarkieB. LettL. SlobbeA. ChaeA. C. JohnstoneC. G. JensenJ. C. McEwanK. DittmerK. ParkerA. WilesW. BlackburneA. LeichterM. LeaskA. PinnapureddyM. JenningsJ. A. HorsfieldR. J. WalkerM. R. EcclesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
C. Stayner
C. A. Poole
S. R. McGlashan
M. Pilanthananond
R. Brauning
D. Markie
B. Lett
L. Slobbe
A. Chae
A. C. Johnstone
C. G. Jensen
J. C. McEwan
K. Dittmer
K. Parker
A. Wiles
W. Blackburne
A. Leichter
M. Leask
A. Pinnapureddy
M. Jennings
J. A. Horsfield
R. J. Walker
M. R. Eccles
An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
description Abstract Meckel syndrome (MKS) is an inherited autosomal recessive hepatorenal fibrocystic syndrome, caused by mutations in TMEM67, characterized by occipital encephalocoele, renal cysts, hepatic fibrosis, and polydactyly. Here we describe an ovine model of MKS, with kidney and liver abnormalities, without polydactyly or occipital encephalocoele. Homozygous missense p.(Ile681Asn; Ile687Ser) mutations identified in ovine TMEM67 were pathogenic in zebrafish phenotype rescue assays. Meckelin protein was expressed in affected and unaffected kidney epithelial cells by immunoblotting, and in primary cilia of lamb kidney cyst epithelial cells by immunofluorescence. In contrast to primary cilia of relatively consistent length and morphology in unaffected kidney cells, those of affected cyst-lining cells displayed a range of short and extremely long cilia, as well as abnormal morphologies, such as bulbous regions along the axoneme. Putative cilia fragments were also consistently located within the cyst luminal contents. The abnormal ciliary phenotype was further confirmed in cultured interstitial fibroblasts from affected kidneys. These primary cilia dysmorphologies and length control defects were significantly greater in affected cells compared to unaffected controls. In conclusion, we describe abnormalities involving primary cilia length and morphology in the first reported example of a large animal model of MKS, in which we have identified TMEM67 mutations.
format article
author C. Stayner
C. A. Poole
S. R. McGlashan
M. Pilanthananond
R. Brauning
D. Markie
B. Lett
L. Slobbe
A. Chae
A. C. Johnstone
C. G. Jensen
J. C. McEwan
K. Dittmer
K. Parker
A. Wiles
W. Blackburne
A. Leichter
M. Leask
A. Pinnapureddy
M. Jennings
J. A. Horsfield
R. J. Walker
M. R. Eccles
author_facet C. Stayner
C. A. Poole
S. R. McGlashan
M. Pilanthananond
R. Brauning
D. Markie
B. Lett
L. Slobbe
A. Chae
A. C. Johnstone
C. G. Jensen
J. C. McEwan
K. Dittmer
K. Parker
A. Wiles
W. Blackburne
A. Leichter
M. Leask
A. Pinnapureddy
M. Jennings
J. A. Horsfield
R. J. Walker
M. R. Eccles
author_sort C. Stayner
title An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
title_short An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
title_full An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
title_fullStr An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
title_full_unstemmed An ovine hepatorenal fibrocystic model of a Meckel-like syndrome associated with dysmorphic primary cilia and TMEM67 mutations
title_sort ovine hepatorenal fibrocystic model of a meckel-like syndrome associated with dysmorphic primary cilia and tmem67 mutations
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/edcafb5f13094ac2bfab71d2db069f8d
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