Prof. Philip L. Beales

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Professor Phil Beales

Current team members:

Dr. Sonia Christou - Senior Research Associate

Dr. Anna Diaz-Font - Research Fellow

Dr. Elizabeth Forsythe - Clinical Research Fellow

Dr. Victor Hernandez - Research Assistant

Dr. Dagan Jenkins - Research Associate

Ms. Sriparna Mukherjee - Research Technician

Dr. Daniel Osborn - Research Associate

Ms. Suzanne Rix – Research Assistant

Dr. Miriam Schmidts - Clinical Research Fellow

Dr. Aoife Waters - MRC Clinical Research Training Fellow

Dr Chiara Bacchelli (GOSGENE) - Senior Research Associate

Dr Estelle Chanudet (GOSGENE) - Senior Research Associate

Main interests:

The Ciliopathies

Our laboratory group is focused on the genetics and mechanism of pathogenesis of a specific category of birth disorders, namely the Ciliopathies which encompasses Bardet-Biedl syndrome (BBS), Jeune Asphyxiating Thoracic Dystrophy (JATD), Cranioectodermal dysplasia amongst many other conditions in this ever expanding group. In fact , we predict there are over one hundred ciliopathies waiting to be defined. These congenital disorders variably affect multiple organs including optical, skeletal, endocrine, genitourinary, renal and nervous systems. The study of these underlying genes and gene products affords a unique opportunity to address the cellular basis for pleiotropy, variability in expression and perhaps even the contribution of gene and protein interaction for functional modelling of complex disease.
We have hypothesised and published supporting evidence that dysfunction of primary cilia is fundamental to the mechanism of BBS and other conditions. Several of the gene products have been placed in the centrosome and basal body (root of the cilium) in most cell types. In fact we have postulated that one such protein, BBS4 may serve as an adaptor to facilitate the loading of cargo onto the molecular motor complex, dynein-dynactin in preparation for intraflagellar transport (IFT). Such transport defects may relate directly to the degeneration of retinal photoreceptors that is characteristic of the syndrome. It is likely that different tissue specific pathomechanisms give rise to other aspects of ciliopathy phenotypes such as defective Wnt signalling in renal parenchymal cystic development, or defective leptin signalling in the control of appetite or impaired hedgehog signalling in polydactyly and short limbs of JATD.
We are therefore concentrating efforts on understanding the normal cellular and developmental roles of these proteins, how they exert differential effects in a tissue-dependent manner and how collectively they give rise to the phenotypes. To this end we have developed several tools including modelling the disease in alternative organisms such as danio rerio, mus musculus, C. elegans, gallus gallus and xenopus laevis. We continue to closely study the human phenotype and have previously reported the genetic epidemiology, the natural history, novel phenotypes, genotype-phenotype correlates, behavioural and neurological aspects of BBS.

The study of ciliopathies has spawned a number of different areas of investigation:

• The role of transcription factors in regulating expression of cilia proteins

• The biology of cilia formation and intraflagellar transport

• The relationship of BBS proteins to the Wnt pathways

• The revelation that some chondrodysplasia (e.g. Jeune ATD, Sensenbrenner)
(CED) are also cilliopathies

We are now actively engaged in ciliotherapeutics to define targets that could be exploited for treatment of these debilitating conditions.

Links:

• LMBBS Society Webpage - http://www.lmbbs.org.uk/

3MC Syndrome

3MC syndrome is a rare recessive disorder named after the unification of three syndromes; Michels, Malpuech and Carnevale. 3MC comprises characteristics craniofacial patterning defects including cleft lip and/or palate, learning difficulties, umbilical and distal limb defects. We recently positionally cloned two genes, COLEC11 and MASP1 both of which encode proteins with key roles in the lectin complement pathway. We demonstrated that COLEC11 has chemotactic properties that regulate cell migration such as the neural crest cells during embryogenesis. This tudy links for the first time complement components with developmental disorders and indicates how we may come to better understand cranofacial development.

Early-onset syndromal and non-syndromal obesity

We maintain a strong interest in the genetics of early-onset obesity largely through the study and understanding of single gene disorders. Our approach is simply that by gaining a greater understanding of the genetics and biology of rare disorders such as BBS, Alstrom, Cohen, Albrights hereditary osteodystrophy and MOMO to name but a few, we can apply the common biochemical pathways to the more complex disorders.
We are currently studying a cohort of children with early onset obesity accompanied by developmental delay/specific learning difficulties. Our aim is to find genetic determinants associated with the obesity component and one approach is to search for submicroscopic chromosomal rearrangements using recently developed array comparative genomic hybridisation (CGH).

GOSGENE

This gene discovery facility was established in 2010 to provide comprehensive novel mutation detection in patients with orphan diseases. GOSGENE is funded by the Specialist Biomedical Research Centre (GOSHICH) and will fund as well as undertake the experimental work required for individual PIs/clinicians from diverse backgrounds who may not have the relevant genetics expertise. We use a wide range of techniques including traditional linkage, autozygosity mapping and increasingly Next Generation sequencing (e.g exome). We also undertake detailed analysis of NGS datasets using dedicated bioinformaticians.

Links:

GOSGENE - http://www.ucl.ac.uk/ich/services/lab-services/gosgene

Collaborations:

• BBS – Nico Katsanis (Duke University), Michel Leroux (Simon Fraser University), Jim Lupski (Baylor College of Medicine).

• Jeune syndrome - Mark Winey (University of Colorado)

• Nephronophthisis - Friedhelm Hildebrandt (University of Michigan), John Sayer (Newcastle University).

• Sensenbrenner - Heleen Arts (Utrecht University)

• 3MC - Sᴓren Hansen

Funding:

• Wellcome Trust

• Medical Research Council

• Kidney Research