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Homozygosity Mapping of Consanguineous Families with Leber S Congenital Amaurosis

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Homozygosity Mapping of Consanguineous Families with Leber S Congenital Amaurosis Int.J.Curr.Microbiol.App.Sci (2015) 4(11): 573-586 ISSN: 2319-7706 Volume 4 Number 11 (2015) pp. 573-586 http://www.ijcmas.com Original Research Article Homozygosity Mapping of Consanguineous Families with Leber s Congenital Amaurosis Abid Ali Shah1*, Kamal Abbasi2 1LAB of GENOMICS, Department of Biochemistry, Faculty of Biological Sciences, Quaid I - Azam University, Islamabad, Pakistan 2Department of Biochemistry, Faculty of Health Sciences, Hazara University, Dhodial Mansehra, Khyber Pukhtunkwa, Pakistan *Corresponding author A B S T R A C T The human eye is a complex organ and is extremely important for vision related functions. Leber congenital amaurosis (LCA) is clinically and genetically heterogeneous disease with autosomal recessive pattern of inheritance and is characterized by severe vision loss present at birth or early childhood. Up to now K e y w o r d s 19 genes have been identified in pathogenic course of LCA, but mutations of few genes are more frequent than others. Interestingly, some of the known LCA genes Homozygosity also cause retinitis pigments and cilia related disorders, which creates extreme Mapping, clinical heterogeneity and poses problems for accurate diagnosis. Two Pakistani Leber families (A and B) with clinical signs like visual impairment since childhood, congenital abnormal movement of eye, flat electroretinogram and abnormal retinal appearance amaurosis, were included in this study. Additionally, affected individuals of both families Autosomal present oculodigital sign, keratoconus and cataract, which are indicators of recessive segregation of LCA phenotype in both families. Both families were subjected to inheritance, candidate gene analysis to test the involvement of currently known LCA genes. Genotyping, One family (A) did not show homozygosity shared by affected individuals for the Linkage all known candidate genes. However, family B revealed homozygosity at RPE65 analysis, genes for two markers, but when typed with additional markers the pattern did not DNA last further. Further analysis showed linkage in a region having spermatogenesis sequencing associated protein 7 (SPATA7; MIM 609868) gene. This region was homozygous in all affected individuals for six markers on chromosome 14 and region contained SPATA7 gene. The exact function of SPATA7 gene is unknown, but studies have shown its role in vesicular transport. The gene is sequenced for the exons which were extensively documented to have mutations in earlier literature, but DNA sequencing did not show any pathogenic variation in all 12 exons of SPATA7 gene. The future identification of pathogenic variation in family A and B require genome wide analysis and next generation technologies respectively. 573 Introduction cones for phototopic vision. The cones are active in bright illumination, whereas the The human eye is a complex organ and by in rods are active in dim illumination (Pearring large most important part of the human et al., 2013). A tiny portion of the retina is body. Eye genesis normally starts at three left behind which is called blind spot. Here week embryo and is developed from all the retinal blood vessels and optic nerve three germinal layers (ectoderm, endoderm separate from retina. Natural blind spot are and mesoderm). The first three years of life completely void of rods and cones so there are important for eye development as is no vision in that spot (Frank and Stephen, tremendous growth occurs during these 2001). years. Normal vision is essential for the growth and development of the visual cortex Retinal diseases in this phase of development. It is normally agreed upon that visual acuity and capacity Retina has numerous cell types and have a develops at first early three years of life high metabolic rate among its tissues so new (Fredrick, 2004). mutation in different proteins of retina leads to the disruption of different physiological Photoreceptors as well functional characteristics and ultimately leads to its deterioration. Special kind of cells is located in retina Hereditary diseases are arranged or which is responsible for detecting light, classified according to observable called photoreceptors. There are two types differences. It includes dystrophies which of photoreceptors. Rods are more abundant has a devastating effect on central retina and in number than cones which are less in then on peripheral retina. The former number. The rods are stretched long and includes age related macular degeneration tube like while cones are small, broad and (ARMD), cone rod degeneration (CORD) pointed. Rods and cones are dispersed in which affect middle retina and leads to unusual numbers throughout the human eye vision loss while the later affect outer with rods more in number than cones. Cones boundary of retina which consists of retinitis are covering the central portion while rods pigmentosa, congenital stationary night are mainly located in the outer segments of blindness (Musarella, 2001). LCA is caused the retina. Just in the central portion of the by both peripheral and central retinal retina there is a small cup or pit like abnormalities leading to colossal loss of depression called fovea or macula, which is vision. Most of the congenital eye disorders responsible for most of vision as has a 100% are bilateral and their mode of inheritance visual sharpness or acuity. Mostly cones are can be autosomal recessive or dominant. present in fovea and are devoid of rods. Sometimes it can be of mitochondrial or X High resolution images are formed when linked in nature. light falls on the fovea portion of the eye (Provis et al., 2013). A famous figure of international repute Theodar Leber discovered a disease from A marked difference in structure occurs not German School of ophthalmology which only between rods and cones, but also was characterized by extreme vision loss between their functions. Rods are more since birth and was found in the offspring of adapted for function in dim light and are healthy individuals. In the coming years he responsible for scotopic vision whereas and others renowned eye specialists noted 574 occurrence of this disease in consanguineous schools across the globe (Marlhens et al., families. Symptoms of the disease were 1997). Advancements in the realms of decreased or nearly extinguished response to human genetics have brought this disease to light reflex, rolling eye movement, but a new horizon, with screening mutations in fundus was of normal architecture at birth approximately 70% of all the LCA showing signs of retinitis pigmentosa. Leber individuals (Perrault et al., 1999). congenital amaurosis has been wrongly diagnosed for cortical blindness because of Genes and loci the normal appearance of fundus at the beginning. It was noticed six years later in a Molecular genetics of LCA the has been report related to infant blindness in which thoroughly explained for the last decade thus the disease was defined as Congenital creating new insights from the research into blindness with extinguished ERG with a Leber congenital amaurosis. So far 19 genes fine appearance of fundus, but often have been implicated in the pathogenic followed by ocular malfunctions such as cause of LCA and these nineteen genes are keratoconus. concerned with different diverse functions of the retina. The LCA genes are GUCY2D Mapping of LCA genes: the dawn of (LCA1), RPE65 (LCA2), SPATA7 (LCA3), linkage era AIPL1 (LCA4), LCA5 (LCA5), RPGRIP1 (LCA6), CRX (LCA7), CRB1 (LCA8), Shomi Bhattacharya was the first who NMNAT1 (LCA9), CEP290 (LCA10), mapped a gene responsible for X linked IMPDH1 (LCA11), RD3 (LCA12), RDH12 Retinitis Pigmentosa on the short arm of the (LCA13), LRAT (LCA14), TULP1 X chromosome (Bhattacharya et al., 1984). (LCA15), KCNJ13 (LCA16), IQCB1 and Later, Peter Humprhies et al. (1990) mapped MERTK (Stockton et al., 1998; Dharmaraj et a gene responsible for autosomal dominant al., 2000; Keen et al., 2003; Perrault et al., RP on a chromosome 3. A ray of hope came 2003). with the new Homozygosity mapping technique which was applied for extended as LCA, despite being relatively clinically and well as closely related families afflicting genetically heterogeneous disease, has been with LCA. Many families of North Africans well studied over the last years. roots were taken and were scanned for Understanding the genetics has also homozygosity mapping via new markers improved lately with mutation in 19 genes called microsatellite markers spanning a now identified for this disease. Analysis of 10 cM region. Subsequently, this the phenotype and establishing a methodology was used to identify the LCA relationship with the genotype remains a locus, LCA1 (Camuzat, 1995, 1996). challenge. The study is based on families with LCA showing autosomal recessive LCA is a collection of congenital retinal inheritance. Candidate genes which are dystrophies manifested by severe vision loss known to be involved in disease are first nystagmus, roving eyes and other checked. The purpose of the study was to retinopathies. The vulnerability of getting investigate the molecular basis of such LCA globally is three out of every 100, 000 disorders whose clinical examination often approximately (Perrault et al., 1996). LCA leads to an imprecise and poor diagnosis. has a significant impact and is responsible Our study is, therefore, important to explore for 20% of all the children attending blind the novel genes and mutations involved in 575 different ocular anomalies as well as and affected individuals, including their growing awareness
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