Doctor Hannah Mitchison
Jeune syndrome – asphyxiating thoracic dystrophy
Jeune Syndrome/ Asphyxating Thoracic Dysplasia (JATD) is a rare recessively inherited disease affecting bone and cartilage development. Surviving children with Jeune Syndrome have “dysproportioned dwarfism” with normal trunk length but shortened limbs and ribs resulting in respiratory deficiency requiring surgical intervention. Associated features include polydactyly, kidney cysts and liver problems. Cilia dysfunction is implicated in Jeune Syndrome since the two known disease-causing genes IFT80 (PL Beales et al, 2007), and DYNC2H1 (N Dagoneau et al, 2009, AE Merrill et al. 2009) encode intraflagellar transport proteins critical for cilia maintenance.
Cilia are hair-like protrusions that extend from the surface of cells throughout the body. Recent advances in ciliary research have identified numerous ciliary genes and proteins and helped to find the molecular causes of a growing number (>20) of inherited diseases involving cilia dysfunction, called “ciliopathies”. Ciliopathies usually cause severe developmental defects and affect children from birth. They indicate an essential role for ciliary proteins in a number of fundamental cell signalling pathways that are critical for embryonic development. Although some of these signalling pathways (e.g. Hedgehog signalling) are found to be commonly altered in some ciliopathies, the pathophysiology behind most ciliopathies remains unclear and therefore targeted treatment options are very limited.
Our group is currently trying to identify new Jeune Syndrome causing genes because only a minority of cases can be explained by mutations in the two known genes. Our aim is to understand the role of cilia in skeletal development and the molecular causes of Jeune syndrome. This work and the development of genetic tests will contribute to improving the diagnosis of Jeune Syndrome, and facilitate carrier testing and prenatal diagnosis for at-risk families. We are currently developing a number of vertebrate model and cell line systems for in vivo investigation of the perturbations to cell signalling processes that arise in Jeune Syndrome. This will yield a greater understanding of the patho-mechanisms underlying this debilitating and often lethal condition and should in future provide potential targets for therapeutic interventions.
We are continuing to actively ascertain new families with Jeune syndrome to contribute to our ongoing genetic studies.
Funding: Action Medical Research, Newlife Foundation, Wellcome Trust
For further information about the project please contact:
Dr Hannah Mitchison email@example.com
Dr Miriam Schmidts firstname.lastname@example.org
Investigators: Suzanne Rix (PhD student), Miriam Schmidts (Clinical Research Fellow), Peter Scambler (PI), Hannah Mitchison (PI), Philip Beales (PI).
Primary Ciliary Dyskinesia (PCD)
Primary ciliary dyskinesia is a recessively inherited childhood disorder affecting the motility of cilia and sperm due to ultrastructural defects, with an incidence estimated at 1 in 15-30,000 live births. It is a chronic and severely debilitating disease most often developing from early infancy then continuing into later years with frequent serious complications. Recurrent infections of the respiratory tract, sinuses and middle ear occur causing chronic bronchitis, rhino-sinusitis and otitis media, and finally bronchiectasis (permanent lung damage). Treatment is symptomatic involving extensive physiotherapy to clear the lungs, ENT management, ear drainage, and antibiotic treatment. Abnormalities of left-right organ development in about half of patients manifesting primarily as isolated situs inversus (Kartagener syndrome) though severe problems arise in ~6% of cases (MP Kennedy et al, 2007). There is also male and female infertility, and hydrocephalus has occasionally been reported.
Early diagnosis and therapeutic intervention improves disease outcomes (M Pifferi et al, 2009), however diagnosis remains difficult and may be delayed due to a lack of disease awareness, since PCD symptoms overlap with other common respiratory problems, and since diagnosis requires specialised testing of ciliary beating and ultrastructure. In 2007 NHS Specialised Sevices funded three UK centres to provide a national diagnostic service for PCD (C O’Callaghan et al, 2007).
In order to understand the molecular genetic basis of this disorder we are working to identify the genes that cause PCD. There is extensive genetci heterogeneity and the known PCD genes only account for ~40% of cases. PCD genes either encode cilia structural proteins required for motility (DNAH5, DNAH11, DNAI1, DNAI2, TXNDC3, DNAL1, RSPH9, RSPH4A, CCDC39 and CCDC40); or proteins located in the cytoplasm that preassemble cilia components (KTU and LCCR50). RPGR and OFD1 are also implicated in x-linked syndromic PCD.
We are continuing to actively ascertain new families with PCD to contribute to our ongoing genetic studies.
We have mapped a number of additional non-overlapping PCD loci where the gene remains to be identified, and we are using next-generation whole exome sequencing in patients for gene identification. We use several approaches to uncover the PCD gene function, including analysis in vertebrate model systems and the biflagellate alga Chlamydomonas.
Human nasal epithelial cell
Inverse heart looping in PCD Zebrafish model
Investigators: Eddie Chung, Hannah Mitchison and Dinu Antony.
Current funding: Action Medical Research, Newlife Foundation
The Ciliopathy Alliance
The Ciliopathy Alliance is an alliance of patient organisations, medical researchers, doctors and other healthcare professionals representing individuals and families affected by ‘ciliopathy’ diseases which are caused by defective cilia. The Alliance’s purpose is to share knowledge and promote awareness of ciliopathies and the respective patient organizations, as well as to encourage, facilitate and fund collaborative research.
Dysfunction of cilia underlies many genetic conditions including Alstrom Syndrome, Jeune Syndrome, Laurence-Moon-Bardet-Biedl Syndrome, Nephronophthisis, Orofaciodigital Syndrome, Polycystic Kidney Disease, Primary Ciliary Dyskinesia, Senior-Loken Syndrome, Retinitis Pigmentosa. Most of these conditions are rare but collectively they have a significant impact in human health, affecting at least one in a thousand people.
The Ciliopathy Alliance was launched on Cilia Awareness day at ICH on November 29, 2010 which was part-funded by the UCL Beacon Bursaries Public Engagement Fund. The Alliance is currently applying for charitable status.
The Ciliopathy Alliance is delighted to announce the 1st International Conference on Cilia in Development and Disease to be held 16-18 May 2012 at the UCL Institute of Child Health, London. Go to http://cilia2012.org/
for further information and to register your
The CA is administered by Tess Harris who may be contacted at +44 207 387 0543 or email@example.com
Ciliopathy Members at the House of Commons on Rare Disease Day
Batten disease (Neuronal Ceroid Lipofuscinosis)
The Neuronal Ceroid Lipofuscinoses are a group of devastating
children’s neurodegenerative diseases often collectively termed Batten disease.
The NCLs are all fatal diseases without cure, characterised by neuronal
cell death in the CNS and neural retina. There are mouse models available for
all the recognised NCL genes except CLN7/MFSD8
(PPT1/CLN1, TPP1/CLN2, CLN3, CLN5,
CLN6, CLN8 and CLN10/CTSD), details at:
We have been investigating the mechanism of retinal dysfunction in the the juvenile form of Batten disease which is caused by mutations in CLN3, a protein of unknown function resident in endo-lysosomes and presynaptic vesicles. The earliest symptom in patients is visual deterioration which starts around 5-8 years of age. Degeneration in the retina is then usually rapid, with photoreceptor loss culminating in blindness often within 2 years. Several years can then pass before the onset of any further signs of the fatal decline in the brain. The subsequent progressive brain atrophy causes psychomotor decline, seizures, dementia and an early death by 20-30 years.
The molecular mechanisms underlying retinal degeneration in Batten disease are not clear, nor is it established whether the mechanism of cell death in the retina is the same as in the brain. We are trying to understand the impact of deficient protein degradative mechanisms in CLN3-deficient cells and how these result in the inflammation and neurogeneration underlying the disorder.
The 13th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease) & 1st Worldwide Meeting of the Batten Disease International Alliance is being held at Royal Holloway University of London, 28th- 31st March 2012. For more information go to: http://www.ncl2012.org/
K Luiro, O Kopra, T Blom, M Gentile, HM Mitchison, I Hovatta, K Thornquist, A Jalanko. Batten disease (JNCL) is linked to disturbances in mitochondrial, cytoskeletal and synaptic compartments. J Neurosci Res, 84:1124-38, 2006.
MA Zariwala, MW Leigh, F Ceppa, MP Kennedy, PG Noone, JL Carson, M Hazucha, A Lori, J Horvath, H Olbrich, NT Loges, A Bridoux, G Pennarun, B Duriez, E Escudier, HM Mitchison, R Chodhari, EMK Chung, LM Morgan, RU De Iongh, J Rutland, U Pradal, H Omran, S Amselem, MR Knowles. Mutations of DNAI1 in Primary Ciliary Dyskinesia: Evidence of founder effect in a common mutation. Am J Resp Crit Care Med, 174:858-66, 2006.
T Ferkol, HM Mitchison, C O'Callaghan, M Leigh, J Carson, H Lie, D Rosenbluth, SL Brody. Current Issues in the Basic Mechanisms, Pathophysiology, Diagnosis, and Management of Primary Ciliary Dyskinesia. In Respiratory Disease in Infants and Children: Challenges and Questions for the Future. Eds. U. Frey and J. Gerritsen. European Respiratory Society Monograph, Maney Publishing, UK, 2006.
JD Cooper, C Russell, HM Mitchison. Progress towards understanding disease mechanisms in small vertebrate models of Neuronal Ceroid Lipofuscinosis. Biochim Biophy Acta, 1762: 873-89, 2006.
S Pohl, HM Mitchison, A Kohlschütter, O van Diggelen, T Braulke, S Storch. Increased expression of lysosomal acid phosphatase in CLN3-defective cells and mouse brain tissue. J Neurochem, 103:2177-88, 2007.
MR Pears, D Rubtsov, HM Mitchison, JD Cooper, DA Pearce, RJ Mortishire-Smith, JL Griffin. Strategies for data analyses in a high Resolution 1H NMR based metabolomics study of a mouse model of Batten Disease. Metabolomics 3:121-136, 2007.
A Bush, R Chodhari, N Collins, F Copeland, P Hall, J Harcourt, M Hariri, C Hogg, J Lucas, HM Mitchison, C O’Callaghan, G Phillips. Primary Ciliary Dyskinesia: current state of the art. Arch Dis Child 92:1136-40, 2007.
K Everett, B Chioza, C Georgoula, A Reece, F Capon, K Parker, C Cord-Udy, P McKeigue, S Mitton, A Pierro, P Puri, HM Mitchison, EMK Chung, RM Gardiner. Genome-wide high density SNP-based linkage analysis of infantile hypertrophic pyloric stenosis identifies loci on chromosomes 11q14-q22 and Xq23. Am J Hum Genet, 82:756-62, 2008.
NT Loges, H Olbrich, L Fenske, J Horvath, R Chodhari, M Fliegauf, H Kuhl, G Baktai, E Peterffy, EMK Chung, A Rutman, C O'Callaghan, H Mussaffi-Georgy, H Blau, L Tiszlavicz, K Voelkel, M Witt, E Ziętkiewicz, J Neesen, R Reinhardt, HM Mitchison, H Omran. DNAI2 mutations can cause primary ciliary dyskinesia with outer dynein arm defects. Am J Hum Genet, 83:547-58, 2008.
DJ Metcalf, AA Calvi, MNJ Seaman, DF Cutler*, HM Mitchison*. Loss of the Batten disease gene CLN3 prevents exit from the TGN of the mannose 6-phosphate receptor. Traffic 9:1905-14, 2008.
C-H Chan, HM Mitchison, DA Pearce. Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models. Hum Mol Genet 17:3332-9, 2008.
VH Castleman, L Romio, R Chodhari, RA Hirst, SC de Castro, KA Parker, P Ybot-Gonzalez, RD Emes, SW Wilson, C Wallis, CA Johnson, RJ Herrera, A Rutman, M Dixon, A Shoemark, A Bush, C Hogg, RM Gardiner, O Reish, ND Greene, C O'Callaghan, S Purton, EM Chung, HM Mitchison. Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities. Am J Hum Genet 84:197-209, 2009.
A Bush, C Hogg, HM Mitchison, M Nisbet, R Wilson. Update in primary ciliary dyskinesia. Clin Pulm Med 16: 219-225, 2009.
TJ Mitchison, HM Mitchison. Cell biology: How cilia beat. Nature 463: 308-9, 2010.
O Reish, M Slatkin, D Chapman-Shimshoni, A Elizur, B Chioza, V Castleman, HM Mitchison. Founder mutation(s) in the RSPH9 gene leading to primary ciliary dyskinesia in two inbred Bedouin families. Ann Hum Genet 74:117-25, 2010.
RM Salek, MR Pears, JD Cooper, HM Mitchison, DA Pearce, RJ Mortishire-Smith, JL Griffin. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses. J Biomol NMR 49:175-184, 2011.
Hannah Mitchison, PhD.
Senior Lecturer in Molecular Genetics Molecular Medicine Unit
University College London (UCL)
Institute of Child Health
30 Guilford Street, London
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