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Title: Monogenic vasculitis of the young
Author: Nanthapisal, S.
ISNI:       0000 0004 8498 9601
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2017
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Vasculitis is characterized by inflammation of the blood vessel wall, which can lead to vascular occlusion, ischaemia, and end-organ injury. The exact causes of most of the primary systemic vasculitides (PSV) are not fully understood; a monogenic cause is strongly suspected in a minority of cases, particularly when similar features occur in first-degree relatives; and/or disease onset is very early in life. The central hypothesis to this thesis is that there are novel monogenic causes of vasculitis affecting the young that may be revealed using next generation sequencing (NGS). The aim of this study was therefore to: 1. use NGS to identify novel candidate genes that could cause vasculitis in children; and 2. to study the potential pathogenic role of any candidate genes identified. Seven probands from 6 families (Sielicka et al.) with different phenotypes of vasculitis were recruited. Whole exome sequencing (WES) was performed in all probands. Homozygous or compound heterozygous loss-of-function mutations in CECR1 (cat eye syndrome chromosome region, candidate 1), which encodes adenosine deaminase type 2, were identified in 4 probands of family A, B and C causing deficiency of adenosine deaminase type 2 (DADA2). Clinical features of DADA2 resemble polyarteritis nodosa. Further investigation in relatives of the probands, and a cohort of childhood PAN revealed an additional 17 affected individuals, 8 of whom were asymptomatic at the time of study. The main clinical features of DADA2 were: cutaneous involvement (66.7%), neurological involvement (52.4%) and immunological involvement (33.3%). Disease was well controlled in 11 patients using anti-TNF-α therapy. Functional studies revealed that ADA2 enzyme activity and CECR1 mRNA expression were decreased in DADA2 in all subjects with homozygous or compound heterozygous mutations (irrespective of whether they were symptomatic or not); and revealed important age-dependent physiological changes in ADA2 activity of healthy controls. DADA2 affects the function and polarisation of macrophages, and may represent a novel vasoprotective pathway. A novel homozygous missense mutation in Protein Kinase C Delta gene (PRKCD) c.1294G > T;p.Gly432Trp was identified in the proband of family D and her sister, who presented with early onset juvenile systemic lupus erythematosus. PRKCD encodes protein kinase C delta, which plays a role in apoptosis and proliferation of multiple cells, including B lymphocytes. The proband of family E presented with early onset cutaneous leukocytoclastic vasculitis, and recurrent bacterial infections. Immunological studies revealed abnormal functional complement assay. A novel homozygous mutation in the complement factor I gene (CFI) was identified. Complement factor I is a C3b/C4b inactivator. The phenotype described herein is therefore novel, since cutaneous leukocytoclastic vasculitis is not typical of CFI deficiency, although recurrent bacterial infections are recognized. The proband of family F presented with digital vasculitis, recurrent infections, and absence of serum C1q. C1q is a protein in the classical complement pathway and mainly produced by macrophages. No mutation in C1q genes was identified using standard Sanger sequencing, or from WES. RNA sequencing also revealed no mutation in any C1q gene; and mRNA expression of all 3 C1q genes was normal. C1q staining of macrophages (using confocal microscopy and intracellular flow cytometric analysis) revealed intracellular accumulation of C1q, suggesting a new syndrome of impaired C1q release, and functional C1q deficiency. These studies confirm my central hypothesis that monogenic vasculitides are an important clinical concern in some children; and yet again demonstrate the diagnostic utility of NGS. Future studies leading directly from the work described in this thesis are also considered.
Supervisor: Brogan, P. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available