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Blindness, Hearing Loss and Brown Crumbly Teeth: Determining the Molecular Basis of Heimler and Heimler Plus Syndromes and Other Related Conditions

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Blindness, Hearing Loss and Brown Crumbly Teeth: Determining the Molecular Basis of Heimler and Heimler Plus Syndromes and Other Related Conditions Blindness, hearing loss and brown crumbly teeth: determining the molecular basis of Heimler and Heimler plus syndromes and other related conditions By Claire Elizabeth Leigh Smith, B.Sc. (Hons) Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds School of Medicine August 2016 The candidate confirms that the work submitted is his/her own, except where work which has formed part of jointly-authored publications has been included. The contribution of the candidate and the other authors to this work has been explicitly indicated overleaf. The candidate confirms that appropriate credit has been given within the thesis where reference has been made to the work of others. ii Jointly authored publications statement Chapter 3 includes data from two jointly authored publications, Ratbi et al. (2015) and Smith et al. (2016b): Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CEL, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR and Van Camp G. (2015) Heimler syndrome is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. American Journal of Human Genetics 97(4):535-545. The author contributed to the publication by carrying out whole exome sequencing library preparation and sequencing analysis of DNA from individual 4505, family AI-202 (labelled as family 4 in the paper) as part of a larger cohort of Heimler syndrome patients. The author submitted findings from sequencing analysis and quality control metrics for the paper and commented critically on the manuscript prior to submission. The other authors provided all other data included in the paper. Smith CEL, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. (2016) Spectrum of PEX1 and PEX6 variants in Heimler syndrome. European Journal of Human Genetics 24 (11) 1565-1571. The author wrote the paper and contributed all data except the details of the phenotype of the patients, which was contributed by the other authors. This paper includes families AI-10 (individuals 1492, 1499 and 1500), AI-146 (3000), AI-186 (4716), AI-16 (2113), AI-152 (3466 and 4922) and AI-71 (2645) which were labelled as families 1, 2, 3, 4, 5 and 6 respectively in the paper). iii Chapter 4 includes data from one jointly authored publication, Smith et al. (2016a): Smith CEL, Murillo G, Brookes SJ, Poulter JA, Silva S, Kirkham J, Inglehearn CF and Mighell AJ. (2016) Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta. Human Molecular Genetics doi: 10.1093/hmg/ddw203 The author wrote the paper and contributed all data except the details of the phenotype of the patients, which was contributed by the other authors. Micro- computerised tomography was carried out in collaboration with Dr. Steven Brookes (University of Leeds). This paper includes family AI-154 (individuals II:2, III:3 and IV:1). iv This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Claire Elizabeth Leigh Smith to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2016 The University of Leeds and Claire Elizabeth Leigh Smith v Acknowledgements Whilst a PhD is an individual achievement, it is a reflection of the valuable support and advice that others provide. Therefore I would like to express my thanks to my supervisors, who have each contributed something different, but equally valued, to my PhD experience. James Poulter has been an ever- present sounding board and has been available to answer my constant questions with a patience and understanding I have rarely observed in anyone else. Chris Inglehearn has been ever encouraging, in the execution of the project, my confidence and in my career. He has also provided an ever-critical eye to all outputs, but has delivered any criticism constructively and in the nicest possible way. Alan Mighell has been invaluable in recruitment of families and in providing phenotypic knowledge. In some cases, he has even been able to guess the causative gene before sequencing. He has also been ever driven to translate the results that I’ve obtained into patient benefit and his perspective helps to reveal the wider impact of genetic diagnosis. His thorough note keeping and clear prioritisation of tasks throughout my PhD have also been of immense value. In conclusion, I appreciate all of my supervisors’ efforts and know how lucky I am to have had such people to guide me. Thanks are also extended to Steve Brookes and Roger Shore, whose respective knowledge of enamel and teeth generally is astounding and has been a very useful resource for me to tap. I would also like to thank everyone who makes level 8 such a nice place to work. My thanks would not be complete without also extending them to my parents. Firstly, thanks to my dad, who encouraged my interest in science and nature, especially meteorology and agriculture, from an early age. Also to my mum who has empathy without bounds and is always enthusiastic, supportive and interested in whatever I am doing. Their pride of my every achievement, however small, has always driven me to try to achieve more. Both have consistently encouraged me to do whatever I think will make me happy and without them, I would not have applied for, nor accepted, my PhD place. vi Last but not least, I would like to thank Seb Tawn. Other than his cookery, holiday booking and foreign language skills, which are all fabulous and make my life far more enjoyable and run more smoothly than it otherwise would, he is also my favourite person and I look forward to being his wife. vii Abstract Enamel is the body’s hardest, most mineralised tissue and protects the underlying tissues of the tooth from the forces exerted during mastication and from bacterial attack. Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. AI can present as either isolated disease or as part of a syndrome. This thesis documents the identification of the genes involved in Heimler syndrome (HS) and in hypomineralised AI. HS is an autosomal recessively inherited combination of sensorineural hearing loss, AI and variable nail abnormalities, with or without visual defects. Biallelic mutations in the peroxisomal biogenesis factor genes, PEX1 and PEX6 were identified through whole exome sequencing (WES) of ten HS patients from seven families. Both proteins were found to be present throughout the retina. Mutations in PEX1 and PEX6 were already known to cause the Zellweger syndrome spectrum disorders (ZSSD), a group of conditions of varying severity. HS represents a mild ZSSD and results from combinations of mutations that include at least one hypomorphic variant, leaving patients with some residual peroxisomal function. For two additional families, mutations in the Usher syndrome (USH) gene, USH2A, were identified, highlighting the phenotypic overlap of HS with the more common USH. One family with autosomal dominantly inherited hypomineralised AI was recruited and DNA from three affected individuals was subjected to WES. DNA copy number variant analysis identified a heterozygous in-frame deletion of exons 3-6 of amelotin. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects. Some of this appeared to be associated with organic material as evidenced by elemental analysis. Both cases in this study highlight the heterogeneity of AI and the importance of a genetic diagnosis for the clinical management of patients. viii Abbreviations AAA+ ATPases associated with diverse cellular activities ACTB actin, beta AD autosomal dominant AI amelogenesis imperfecta AMBN ameloblastin AMEL amelogenin, refers to both copies present on chromosomes X and Y in humans AMELX amelogenin, X linked AMELY amelogenin, Y linked AMTN amelotin APS ammonium persulphate AR autosomal recessive ATAD3B ATPase family, AAA domain containing 3B ATAD3C ATPase family, AAA domain containing 3C ATP adenosine triphosphate BAM binary alignment/map BCA bicinchoninic acid BLAST Basic Local Alignment Search Tool BLAT BLAST-like alignment tool BMP bone morphogenetic protein bp base pair BWA Burrows-Wheeler aligner CADD Combined Annotation Dependent Depletion CAPN5 calpain 5 cDNA complementary deoxyribonucleic acid cM centiMorgan COL17A1 collagen, type XVII, alpha-1 CNV copy number variant CSNK1A1 casein kinase 1 alpha 1 C4orf26 chromosome 4 open reading frame 26 D domain DAB 3, 3-diaminobenzidine ix dbSNP database of single nucleotide polymorphisms and multiple small- scale variations ddNTPs dideoxynucleoside triphosphates DEJ dentino-enamel junction DLX3 distal-less homeobox 3 DMSO dimethyl sulphoxide DNA deoxyribonucleic acid dNTPs deoxynucleotide triphosphates ddNTPs dideoxynucleotide triphosphates DSPP dentin sialophosphoprotein EDTA ethylenediaminetetraacetic acid EDX energy dispersive X-ray spectroscopy EMP enamel matrix protein ENAM enamelin ER endoplasmic reticulum ERS enamel renal syndrome EVS Exome Variant Server ExAC Exome Aggregation Consortium FAM20A family with sequence
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