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Meckel-Gruber syndrome

Characterization of a large animal model of autosomal recessive polycystic kidney disease Mike Eccles, Pathology Department, University of Otago. Meckel-Gruber syndrome.

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Meckel-Gruber syndrome

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  1. Characterization of a large animal model of autosomal recessive polycystic kidney diseaseMike Eccles,Pathology Department,University of Otago

  2. Meckel-Gruber syndrome Meckel-Gruber syndrome - severe fetal developmental disorder. Clinical hallmarks are occipital meningoencephalocele, cystic kidney dysplasia, fibrotic changes of the liver, hepatic ductal dysplasia and cysts, and polydactyly (sometimes retinal anomalies)

  3. Other polycystic/cystic kidney diseases

  4. Other organ involvement • ADPKD - Kidney cysts, liver cysts, intracranial aneurysm • ARPKD - Kidney cysts, liver cysts, Liver fibrosis, pancreatic cysts, lung hypoplasia

  5. Localized cyst formation

  6. PCKD in NZ sheep • Reports of polycystic kidneys in newborn lambs sporadically in NZ Romneys since 1950 (Hancock, 1950) • Winton Coopworth PCKD spring 2000 • Rangiora Perendale PCKD spring 2001 • Also in Romney flock, spring 2004

  7. First samples DNA fingerprinted in Nov 2000 Suspected carrier rams (3) and ewes were transported to Invermay (2001) Recessive transmission demonstrated 2001 Ovine PCKD (Otago) 96-642 96-642 Green 3 Green 4 K3A kidneys K3B K4 kidney

  8. Polycystic kidneys from affected sheep Johnstone et al. 2005 NZ Vet J 53:307-314

  9. Otago PCKD Lamb Phenotype • Non-euthanased lambs survive only ?hours? • Kidney; fluid-filled cysts 1-5mm diameter. Medullary cysts fusiform, otherwise little cortico-medullary distinction. No urine in bladder • Liver; Extensive portal fibrosis, bile duct dilated (hyperplasia), ditto pancreatic duct & cystic • Pancreas; no normal pancreas structure • Epidydimis; cystic • Some indications of hydrocephaly

  10. Autozygosity; two alleles alike because of a common ancestor. Autozygosity mapping first suggested by Lander and Botstein in 1987 Woods et al, 2004 (the number of consecutive homozygous SNPs) Autozygosity mapping

  11. 14 affected and 1 carrier DNAs analyzed with SNP50 beadchip 1, 98-8587, unknown father, unknown mother, male, coopworth 2, 189/190, 98-8587, 8001, male, coopworth 3, 07/498, 06-5 (twin of 189/190), 01-43, male, coopworth 4, 07/497 (twin of 07/498), 06-5, 01-43, male, coopworth 5, 95/97, 98-8587, 01-3, male, coopworth 6, 06-10, 98-8587, 01-40, male, coopworth 7, 07/195, 06-26, 01-23, female, coopworth 8, Ewe 4 lamb, unknown father, ewe 4, male, coopworth 9, Ewe 5 lamb, unknown father, ewe 5, male, coopworth 10, Ewe 7 lamb, unknown father, ewe 7, sex unknown, coopworth 11, Ewe 8 lamb, unknown father, ewe 8, sex unknown, coopworth 12, Ewe 9 lamb, unknown father, ewe 9, male, coopworth 13, K3 Lamb A (twin of K3 lamb B), 96-642, K3, sex unknown, coopworth 14, K3 Lamb B (twin of K3 lamb A), 96-642, K3, sex unknown, coopworth 15, K4 Lamb Single, 96-642, K4, sex unknown, coopworth Genotype call rate was 99.4% (54,291 SNPs). 14 out of 15 DNAs worked.

  12. Chromosome regions of extensive autozygosity in 13/14 samples • Chromosomes 4, 9, 11; • Chromosome 4 bp 72380844 to bp 72769785 (388,941 bp segment) • Chromosome 9 bp 87942007 to 89018996 (1,076,989 bp segment) • Chromosome 11 bp 27807356 to bp 29412465 (1,605,109 bp segment)

  13. Ovine-human comparison

  14. *

  15. Genes in the regions of interest • Chromosome 4, Genes: 3-hydroxyisobutyrate dehydrogenase, Even skipped homeobox 1 (EVX1). • Chromosome 9, Genes: Transmembrane protein 67 (TMEM67), RNA binding motif protein 12B. • Chromosome 11, Contains 60 genes.

  16. Where is the mutation? • Bron Lett is sequencing TMEM67 in affected and carrier sheep. • Planning to sequence larger (~1Mb) region (multiple loci) in affected and carrier sheep to determine SNPs. • Role of primary cilia (Assoc. Prof. Tony Poole)

  17. TMEM67 (MKS3) • Meckel–Gruber Syndrome proteins MKS1 and MKS3 (meckelin) interact and are required for primary cilium formation (Dawe et al, 1997) • Mutations in TMEM67 also cause of COACH syndrome(CEREBELLAR VERMIS HYPO/APLASIA, OLIGOPHRENIA, CONGENITAL ATAXIA, OCULAR COLOBOMA, AND HEPATIC FIBROSIS), and are found in Bardet Biedel syndrome

  18. Otago University David Markie Cherie Stayner Bron Lett Tony Poole Kim Parker Mike Jennings Les McNoe Jane Wilson Cathal Mahon Samara Bretherton AgResearch John McEwan Russell Adam Wayne Smaill Theresa Wilson Massey Bob Jolly Alasdair Johnstone Auckland Sue McGlashen Cynthia Jensen Funding Ovita/TEC C. Alma Baker Trust NZ Kidney Foundation UoO/AgResearch Acknowledgements

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