Genetic dissection of biomineralisation defects and associations with retinal degeneration
This Wellcome Trust funded group was established in 2008 to synergistically build on the work of the Leeds Biomineralisation and Vision Research groups. Sensory organ and tooth hard tissue development are not obviously linked. However, we have ascertained patient cohorts with novel syndromes involving recessively inherited Amelogenesis Imperfecta (AI – a congenital defect of enamel) and two different forms of retinal degeneration. This poses intriguing questions as to the nature of the genetic defects which could affect the development and function of such diverse tissues. We are testing the hypothesis that there is a molecular pathway critical to both enamel biomineralisation and retinal function.
Much is known about the genetic basis of retinal degeneration with greater than 129 genes and 181 loci implicated, giving insight into how pivotal proteins operate in molecular pathways. By comparison, relatively little is known about the causes of AI and how these relate to biomineralisation in other human hard tissues. To date only 3 genes have been described for recessive forms of AI. Accordingly, families with recessively- inherited non-syndromic AI are also being studied to gain a better understanding of this relatively under- researched inherited disorder.
In early 2009 we reported that Jalili Syndrome, which is characterised by early onset cone rod dystrophy leading to visual impairment and AI, is caused by mutations in CNMM4, a putative metal ion transporter1. Further studies are ongoing to understand the functions of this gene that is critical to both retinal health and biomineralisation.
Another syndrome characterised by failure of enamel biomineralisation and retinal degeneration is being investigated by a genetic approach to identify the genes and proteins involved and gain insight into how these might relate to known molecular pathways. The associated clinical phenotypes are being characterised further. Our preliminary data confirms the existence of further recessive AI loci.
The approach described will allow us to make discoveries of relevance to human health and gain novel insight into potential molecular links between biomineralisation and retinal function.
Figure 1. Amelogenesis Imperfecta is associated from infancy with pain, functional failure, poor aesthetics, and a markedly negative psychosocial impact with low self-esteem from an early age. Poor tooth quality limits treatment options and early tooth loss exacerbates the morbidity further.
Figure 2. Retinal degeneration leads to childhood blindness with visual loss evident pre-school.
Parry DA, Mighell AJ, Elsayed W et al. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal recessive cone-rod dystrophy and amelogenesis imperfect. American Journal of Human Genetics. Feb 2009.