Neurological and Ophthalmological Genetics
Neurological genetics is the study of the genetic causes of neurological diseases, which can affect either central nervous system (brain and spinal cord) or the peripheral nervous system. Ophthalmological genetics is the study of the genes responsible for ocular genetic disorders. Because the neural part of the retina is an extension of the brain, many neurological disorders have an ocular component. To develop new ways of treating both diseases, scientists study the developmental, metabolic and environmental factors regulating the expression of the genes involved in the diseases.
The mammalian eye is a complex organ that develops from mesoderm, ectoderm, and endoderm, and contains multiple cell types including neuronal cells. Inherited eye diseases are the main cause of blindness in the developed countries and although they can affect all parts of the eye (including the lens, cornea and optic nerve), retinal disorders are the most common. The genetic defects can cause dysfunction of structural proteins, the phototransduction, color perception or metabolic pathways and can also result in full or partial absence of anatomical structures e.g., aniridia (absence of iris caused by a mutation in the Pax6 gene).
The rod photoreceptor cells must maintain the discs in their outer segments in a precisely ordered structural arrangement to enable efficient light detection. The integrity of this structure is maintained by tetramers formed by RDS/peripherin and ROM1 proteins. Mutations in ROM1 gene cause retinitis pigmentosa (RP), while changes in RDS protein cause a number of clinically different diseases (e.g., macular dystrophy, rod -cone dystrophy, and RP).
The main component of the rod outer segment discs is rhodopsin (Rho) that plays a central role in phototransduction by capturing photons and initiating a signal transduction pathway in the photoreceptor cells. Mutations in rhodopsin cause retinitis pigmentosa.
The phototransduction in the photoreceptor cells is dependent on a sequential activation of GTP interacting proteins such as: transducin, guanylate cyclase, phosphodiesterase, and GTPase regulator. Mutations in these genes cause Leber's congenital amaurosis (LCA1), cone-rod dystrophy (CORD6), retinitis pigmentosa, and congenital stationary night blindness (CSNB3). Desensitization of G-protein coupled receptors is carried out by arrestin which also functions in endocytosis of the receptors. Although no mutations have been demonstrated in arrestin to date, it can form stable complexes with rhodopsin that cause retinal degeneration and can be an important factor in pathology of Rho-linked RP (approx. 25% of RP cases). Signal transduction from the receptor to the brain depends on the neurotransmission. The transmission of signal from the photoreceptors to retinal neurons is affected by mutations in the NYX gene causing X-linked congenital stationary blindness (CSNB1).
Rod outer segments are constantly being renewed and the cell components are being recycled. Therefore, genes whose products are involved in membrane transport and phagocytosis, such as the ABCR gene (mutations cause Stargard's macular dystrophy) or intracellular transport, such as myosin (MYO7) (interacts with actin filaments and mutations cause Usher syndrome) are important for the function of the photoreceptors. Mutations in ubiquitously expressed genes not always affect all of the tissues in the body, for example changes in tissue inhibitor of metalloproteinase 3 (TIMP3). Haploinsufficiency of TIMP3 causes Sorby's fundus dystrophy by inducing thickening of the Bruch's membrane by an unknown mechanism and does not affect any other tissues. Metabolic abnormalities in the retina can also be caused by excessive accumulation of the metabolites in the photoreceptor cells. Retina and choroid are affected by mutations in the mitochondrial ornithine aminotransferase that cause Gyrate atrophy.
Mutations in some genes cause both neurological and ophthalmic disorders, e.g. Leber's hereditary optic neuropathy (LHON) a disease with mitochondrial inheritance. There is, however, a significant group of neurological defects with no ophthalmic component (e.g., Huntington's disease).
Neurological defects can result from mutations in genes encoding components of ion transport channels or intra- and inter-cellular signalling, extracellular matrix or cytoskeleton, or result from haploinsufficiency during embryonic development and from mutations leading to neuronal cell death.
Ion channels are important for signal transduction in muscles and along the neurons. The main types of channels involved are sodium, potassium and calcium. Mutations in the genes encoding the proteins forming the channels can cause lack of the normal channel inactivation (e.g. sodium ion channel in paramyotonia congenita), increase in ion (chloride) conductance leading to repetitive firing (myotonia congenita - CLCN1) and altered kinetics and/or interference in ion (potassium) channel assembly (Episodic ataxia - KCN1).
Neuronal dystrophies can also be caused by mutations in cytoskeleton proteins, e.g. dystrophin in Duchenne muscular dystrophy or in structural proteins such as collagens or laminin in congenital muscular dystrophies, leading to abnormalities of sarcolemma and basement membrane structure in muscle cells.
A number of inherited disorders (Huntington's disease, Kennedy's disease or spinocerebral ataxia 6) are caused by expansion of polyglutamine repeats. Such changes in proteins lead to a progressive neurodegeneration with symptoms specific for a particular disease. This process is attributable to accumulation of inclusion bodies containing abnormal protein and subsequent neuronal cell death. Although the genetic problem has been identified in these diseases, the actual pathway leading to cell death is not clear.
Both neurological and ophthalmological genetics will benefit from the completion of the human genome sequencing, as the identification of the candidate genes can be done in a relatively short time after the initial linkage analysis.
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