PUBLICATION

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

Authors

Stayner, C., Poole, C.A., McGlashan, S.R., Pilanthananond, M., Brauning, R., Markie, D., Lett, B., Slobbe, L., Chae, A., Johnstone, A.C., Jensen, C.G., McEwan, J.C., Dittmer, K., Parker, K., Wiles, A., Blackburne, W., Leichter, A., Leask, M., Pinnapureddy, A., Jennings, M., Horsfield, J.A., Walker, R.J., Eccles, M.R.

ID

ZDB-PUB-170512-10

Date

2017

Source

Scientific Reports 7: 1601 (Journal)

Registered Authors

Horsfield, Jules

Keywords

Clinical genetics, Experimental models of disease

MeSH Terms

Animals
Dandy-Walker Syndrome/genetics*
Dandy-Walker Syndrome/pathology
Sheep
Golgi Apparatus/metabolism
Epithelial Cells/metabolism
Homozygote
Abnormalities, Multiple/genetics*
Abnormalities, Multiple/pathology
RNA, Messenger/genetics
RNA, Messenger/metabolism
Zebrafish
Genetic Loci
Pancreatic Cyst/genetics*
Pancreatic Cyst/pathology
Mutation, Missense/genetics
Chromosomes, Mammalian/genetics
Membrane Proteins/chemistry
Membrane Proteins/genetics*
Hepatorenal Syndrome/genetics*
Hepatorenal Syndrome/pathology
Cilia/pathology
Amino Acid Substitution
Base Sequence
Disease Models, Animal
Mutation/genetics*
Kidney/pathology

(all 27)

PubMed

28487520 Full text @ Sci. Rep.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-tmem67	standard conditions	10-13 somites	brain morphology, abnormal	Fig. 5
AB + MO1-tmem67	standard conditions	10-13 somites	notochord kinked, abnormal	Fig. 5
AB + MO1-tmem67	standard conditions	10-13 somites	notochord morphology, abnormal	Fig. 5
AB + MO1-tmem67	standard conditions	10-13 somites	otic placode morphology, abnormal	Fig. 5
AB + MO1-tmem67	standard conditions	10-13 somites	somite increased width, abnormal	Fig. 5
AB + MO1-tmem67	standard conditions	10-13 somites	whole organism anterior-posterior axis shortened, abnormal	Fig. 5

1 - 6 of 6

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Mutations / Transgenics

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Meckel syndrome			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
tmem67	MO1-tmem67	MRPHLNO

Fish

Fish
AB + MO1-tmem67

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Stayner et al., 2017 ZDB-PUB-170512-10 PMID:28487520

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

Stayner et al., 2017

ZDB-PUB-170512-10
PMID:28487520