Genetic Basis of Nystagmus: Review of Literature About the Affected Families from Balochistan Province

REVIEW ARTICLE ISRA MEDICAL JOURNAL | Volume 9 - Issue 6 | Nov - Dec 2017

Genetic Basis of Nystagmus: Review of literature about the affected families from Balochistan Province

Muhammad Musawir Khan Kakar1, Abdul Malik Tareen2, Imran Shabir3, Hafeezullah Khan1, Naqeeb Jogizai4, Waqar Arshad4

ABSTRACT

Nystagmus is an ocular disorder which is defined as an uncontrolled oscillatory moment of the eyes. Familial Nystagmus with certain eye disorders are heterogeneous based on genetic analysis and very little is known about the underlying mechanism. Studies on different genetic issues show that Pakistan has a populace with a flexible pool of genetics engaged with causing maladies and, in this manner; is inclined to be explored for novel Genes. Although various genes have been reported to be the cause of nystagmus either explicitly or implicitly. To date various genes have been put on record that are responsible to cause nystagmus that include but are not limited to FRMD7, TYR, CNGA3, GPR14, NYS3, NYS4, NYS5, NYS6, NYS7, CNGA3 & CNGB3, GNAT2, PDE6C & PDE6H .yet Pakistan is in a dire need of molecular investigation of nystagmus. We therefore reviewed in this article the genes pool responsible for causing nystagmus. KEYWORDS: Nystagmus; pathophysiology; Familial Nystagmus, heterogeneous, novel gene.

HOW TO CITE THIS: Kakar MMK, Tareen AM, Shabir I, Khan H, Jogizai N, Arshad W. Genetic Basis of Nystagmus: Review of literature about the affected families from Balochistan Province. Isra Med J. 2017; 9(6): 435-38

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INTRODUCTION eyes, defined as repetitive to and fro movement. Itmay be physiological or pathological and may be congenital or In this article, we have attempted to review the genetic basis acquired.1 of nystagmus. We have explained nystagmus and the causes TYPES OF NYSTAGMUS behind nystagmus. In the beginning we have discussed the Nystagmus is generally classified into three broad categories: types of nystagmus, then this is followed by Discussion on a) Congenital / infantile nystagmus: It is an x-linked genetics involved in nystagmus including a comprehensive disorder of the eyes which happens at birth or assessment of the different genes (FRMD7, TYR, CNGA3, soon after. Congenital nystagmus may be found GPR14, NYS3, NYS4, NYS5, NYS6, NYS7, CNGA3 & CNGB3, linked to other disorders in a syndromic form.2-4 GNAT2, PDE6C & PDE6H), their likely role in the development b) Induced nystagmus. This nystagmus type, as the name of nystagmus furthermore, the subtle elements of the variants indicates, is physiologically induced and the probable causes of published in these genes have been reviewed. which are: thermal stimuli, visual stimuli, and rotation of the body Clinical Manifestations Nystagmus is a- an ailment of the c) Acquired nystagmus: It is the form of nystagmus which occurs due to the factors other than inducing factors such as drug toxicity. 1. M.Phil. Scholar of Microbiology Spontaneous Nystagmus: Spontaneous nystagmus has been 2. Professor of Microbiology defined as that nystagmus which appears in the upright University of Baluchistan, Quetta, Baluchistan, Pakistan position of the head, in darkness and at least 3 feet away from 3. Assistant Professor of Bioinformatics and Biotechnology any form of stimulus. It has not been included in the above 4. Ph.D. Scholar of Bioinformatics and Biotechnology classification. Islamic International University Islamabad, Pakistan Etiopathogenesis: Clinically, nystagmus can be characterized by the plane/s of oscillation, the direction/s of gaze at which Correspondence to: it occurs, the degree of conjugacy. A reasonable indicator of Muhammad Musawir Khan Kakar the nystagmus can be obtained by merely viewing the eyes. M.Phil. Scholar of Microbiology This can be further supplemented by the use of Frenzel’s University of Baluchistan, Quetta, Baluchistan, Pakistan glasses, electro-nystagmus consist of a slow drift of the eyes Email: [email protected] in one direction followed with a fast corrective movement in the neutral position, and it is termed as jerk nystagmus. When Received for Publication: 17-10-16 the eyes oscillate like a sine wave, the nystagmus is termed as Accepted for Publication: 09-10-17 pendular nystagmus.

435 Muhammad Musawir Khan Kakar et al. ISRA MEDICAL JOURNAL | Volume 9 - Issue 6 | Nov - Dec 2017 DISCUSSION FRMD7-FERM DOMAIN CONTAINING 7: The human FRMD7 gene contains 12 exons, encodes a 714-buildup polypeptide. 28 A cohort study that was conducted particularly on blind nystagmus causing transformations have been distinguished in or partially sighted children who were over 15 years in the FRMD7 gene up to now .a locus for x-linked sporadically Denmark estimated the prevalence of nystagmus. A study overwhelming CIN revealed by kerrison et al. Xq26-q27 in 3 was conducted in the Netherlands among 220,802 army clans and a clan with X-Linked overwhelming CIN by Cabot et recruits, who were primarily excluded from service due to al. at Xp11.4-p11.3 accounts for such a mutation.2, 3 their deteriorated visions. It was later reported that 117 were In a recent study in 2015 carried out by Jae-Hwan Choi and eventually discharged because of nystagmus.5 Another study his co-workers, they identified a novel start codon mutation conducted showed that elementary school children who were within the FRMD7 gene of 2 Korean families. They revealed in first grade in Malmö, Sweden between 1941 and 1959. The that mutation spectrum of FRMD7 was the causative agent result of this study showed that a total frequency of 1 in 1500 of IIN.9 In 2011, Arif O. Khan and his co-workers carried out a children; boys: 1 in 1000 and girls: 1 in 2800.6 study on a family in soudi arabia. They found mutation in two overwhelmed individuals in their findings that inFRMD7 splice GENES INVOLVED IN CAUSING NYSTAGMUS mutant (c.1050 + 5 G>A).10 In yet another study carried in 2012 by Hu Ying in a long four generation Chinese family in which Many of the congenital or hereditary pigmentary disorders of a novel mutation was detected preceding exon3 of FRMD7 in the skin are basically associated with pigmentary abnormalities affected individuals whereas healthy individuals had no such in the eye, such as changes in pigmentation of the fundus or iris mutations that confirms the involvement of FRMD7 in causing heterochromia. However, more commonly, the associated eye congenital nystagmus.11 finding is actually a defect in ocular motility, i.e., strabismus and nystagmus, recognizing the neuro-developmental etiology GPR143 GENE: The human GPR143 gene - plays a signaling leading to nystagmus is of prime significance for understanding role, consists of 9 exons which encode a 439-kDa protein of the pathophysiology of nystagmus. Genetic heterogeneity 404 aa.12 About more than 100 mutations of GPR143 have is well established in Nystagmus and so far various genes been identified. Most of the alterations in this gene have been (FRMD7, TYR, GPR14, NYS3, NYS4, NYS5, NYS6, NYS7, CNGA3 reported to be associated with OA but some mutations have & CNGB3, GNAT2, and PDE6C & PDE6H) have been discovered. been noted to be associated with CN.13 In a very recent study Mutations in these genes are thought to possess an important in 2016, Liu J conducted a study on a large sixth-generation role to play in causing nystagmus. Chinese family and characterized nystagmus .in their study they reported a new gene other than the FRMD7 gene and reported a novel large deletion in exon 3 -9 of the GPR143 gene TYR GENE: TYR is a gene that instructs the production of a suggesting that not only FRMD7 but variations in other genes protein called tyrosinase which is an enzyme responsible for such as GPR143 are also one of the main causes of nystagmus.14 various steps in melanin production in specialized cells called melanocytes. Melanin is a pigment that confers skin, hair, and NYS3 GENE & NYS4 GENE: It is a gene that is present at a locus nails a specific colors.it is also found in retina, where it plays on chromosome number 13.in 2003, Ragge NK. et al. carried a role in normal vision. Thus any mutations in TYR can cause out a phenotypic study of a unique four generation family with problems to the vision system such as nystagmus. To date nystagmus. They identified affected family members who had almost 320 mutational changes have been noticed for TYR developed nystagmus in the first 24 months of life. Haplotype gene in various ethnic populace around the world reported construction and analysis of recombination events linked the in the Human Genome Mutation Database (HGMD). Changes disorder to NYS4 on chromosome 13q31-q33.15 in the TYR gene is a fundamental reason behind albinism of various types i.e. type 1 Oculocutaneous Albinism termed as CNGA3 & CNGB3, GNAT2, PDE6C & PDE6H GENE: Mutations type 1A (OCA1A). in any of these genes cause a disease known as Achromatopsia In a study, Faravareh Khordadpoor-Deilamani, et al. in 2015 (ACHM) -a congenital, retinal disease that ultimately leads to found TYR gene mutations which were identified in 14 (app. nystagmus.. Zelinger L and his co-workers in 2015 identified 60%) albinism patients.7 Another study was carried by Liu N et 148 ACHM patients from 57 Israeli and Palestinian families; al. In 2014. In their study they screened a total of 30 individuals there were 16 CNGA3 mutations (5 novel) in 41 families and 5 with 100 healthy individuals as control for mutations in TYR CNGB3 mutations (1 novel) in 8 families.16 gene from a Chinese family affected with OCA. They identified Yet again in 2015 Liang X and his co-workers studied the 4 novel mutations out of a total of 20 mutations. Of the total pathogenic mutations in Chinese patients with ACHM. In their affected individuals 83 % individuals were TYR compound study they included fifteen patients from 10 unrelated families. heterozygous; and 6% carried homozygous TYR mutations; and They observed Nystagmus in all the patients. In their study 10 % were heterozygous.8 they amplified the exons of various genes. CNGA3 changes It is not only the TYR gene that could be held responsible to were distinguished in 13 affected individuals from 8 clans. cause low pigmentation and thus resulting in nystagmus rather Sequencing uncovered 7 novel missense transformations, 23 several other genetic players are also responsible for a lower percent of these were novel deletion mutations, whereas 30 rate of melanin production resulting in an uncontrolled eye percent of these were already revealed transformations.17 movement. Among the five causative genes (CNGA3, CNGB3, GNAT2,

436 Muhammad Musawir Khan Kakar et al. ISRA MEDICAL JOURNAL | Volume 9 - Issue 6 | Nov - Dec 2017 PDE6C and PDE6H) of ACHM, Mutations in CNGA3 and CNGB3, in causing nystagmus. accounts for 25 % and 40–50 % respectively in multiple ethnic groups.18 Mutations in CNGA3 are considered the most RECOMMENDATIONS common cause of ACHM.19 PDE6H is yet another gene that encodes the inhibitory γ subunit of the cone photoreceptor In order to know the diagnosis and medications of Congenital PDE and mutation is this gene has been reported to be another Idiopathic Nystagmus, in depth analysis is to be brought into rare cause of ACHM.18, 20 consideration to demonstrate causes of nystagmus. A detailed Gene analysis would also provide great promise for suitable GENETIC BASIS OF NYSTAGMUS IN PAKISTANI POPULATION. therapies to the individuals with nystagmus associated disorders such as Achromatopsia. The associated genes should Pakistan comprises a greater and diverse nature of ethnicity be considered as main players of causing nystagmus and these and has been amongst the most variant nature of countries genes should be checked for new variations. populated with about 18 ethnic origins who speak almost about 60 or more languages. All these people have a greater CONTRIBUTION OF AUTHOR hierarchical linkages with Arabian, European, and Indian ancestry. In the major ethnic population in Pakistan such as Kakar MMK: Conceived Idea, Data Collection, Literature Baloch, Pashtun, Hazara and Balti have a higher intra-family Review, Manuscript Writing marriages history that makes about 60 or more percentage Tareen AM: Data Interpretation, Manuscript final reading and of the country to be comprised of high rate of consanguinity approval with a large family size. Due to this high ratio of consanguinity Shabir I: Statistical Analysis in Pakistan, its population is considered to be rich for genetic Khan H: Data Collection linkage studies Jogizai N: Literature Search Arshad W: Designed Research Methodology TYR GENE Disclaimer: None. About 9 pathogenic transformations could be noted Conflict of Interest: None. for TYR gene in mostly sporadic cases from Pakistan however Source of Funding: None. balochistan remains unstudied and there has been almost lack of any such studies regarding TYR gene transformations. REFERENCES In a study Shah, SA and his co-workers in 2014 reported a 4 member’s Pakistani family with OCA. In the afore-mentioned 1. Straube A, Bronstein A, Straumann D. Nystagmus and family they identified, after screening the TYR gene, substitution oscillopsia. Eur J of Neur. 2012; 19: 6–14. of p.Ile198Thr that in fact is a type of unique missense variant. 2. Kerrison JB, Arnould VJ, Barmada MM, Koenekoop RK, Where as in the same study some 90 unrelated individuals, Schmeckpeper BJ, Maumenee IH. A gene for autosomal who were not diagnosed with any disorder of the eyes, were dominant congenital nystagmus localizes to 6p12. screened as control for TYR mutation and resultantly these Genomics. 1996; 33 (3):523-26. individuals showed no mutation in the sequence of the TYR gene at this location. They also reported an eight member’s 3. Cabot A, Rozet JM, Gerber S, Perrault I, Ducroq D, Smahi A, Pakistani family with 4 substitutions of missense type et al. A gene for X-linked idiopathic congenital nystagmus in TYR gene through Linkage analysis.21 (NYS1) maps to chromosome Xp11.4-p11.3. Am J Hum In a study it was confirmed that nystagmus remains one of the Genet. 1999; 64 (4):1141-46. leading causes of the low vision disorders and that the low 4. Kerrison JB, Vagefi MR, Barmada MM, Maumenee IH. vision defects due to nystagmus are more obvious in children Congenital motor nystagmus linked to Xq26-q27. Am J under 16 years of age in NWFP. Shah SP and his co researchers Hum Genet. 1999; 64 (2):600-607. reiterated that Retinal diseases including nystagmus are more 5. Hemmes GD. Hereditary nystagmus. Am J Ophthalmol 22 common in Balochistan and NWFP. 1924; 10:149-50. In another study carried out at district Lasbella by Khalil and his co-workers showing that Out of 25,437 children attedning 6. Forssman B, Ringnér B. Prevalence and inheritance of schools,22.84% had ocular problems in which 26 children had congenital nystagmus in a Swedish population. Ann Hum nystagmus making it a low propertion i.e 0.10% of all the school Genet 1971; 35:139-47. attending patients causing low occular vision defects.22, 23,24 7. Khordadpoor-Deilamani F, Akbari MT, Karimipoor M, Javadi G. Sequence analysis of tyrosinase gene in ocular CONCLUSIONS and oculocutaneous albinism patients: introducing three novel mutations, Mol Vis. 2015; 21: 730–35. Studies on various genetic disorders demonstrate that 8. Liu N, Kong XD, Shi HR, Wu QH, Jiang M. Tyrosinase gene congenital nystagmus is a disorder for which a versatile pool mutations in the Chinese Han population with OCA1. of genes are involved in causing this disorder, furthermore; Genet Res (Camb). 2014;96:14. Pakistan has been considered amongst the most unstudied part of the world on the investigations of the genetics involved 9. Jae-Hwan Choi, Jin-Hong Shin, Je Hyun Seo, Jae-Ho

437 Muhammad Musawir Khan Kakar et al. ISRA MEDICAL JOURNAL | Volume 9 - Issue 6 | Nov - Dec 2017 Jung and Kwang-Dong Choi. A start codon mutation of Sylla E, et al. Total colourblindness is caused by mutations the FRMD7 gene in two Korean families with idiopathic in the gene encoding the alpha-subunit of the cone infantile nystagmus, Sci Rep. 2015; 5: 13003. photoreceptor cGMP-gated cation channel. Nat Genet. 10. Khan AO, Shinwari J, Al-Sharif L, Khalil DS, Al Tassan 1998;19(3):257–59. N. Prolonged pursuit by optokinetic drum testing 19. Li S, Huang L, Xiao X, Jia X, Guo X, Zhang Q. Identification in asymptomatic female carriers of novel FRMD7 of CNGA3 mutations in 46 families: common cause of splice mutation c.1050 +5 G>A. Arch Ophthalmol. achromatopsia and cone-rod dystrophies in Chinese 2011;129(7):936-40. patients. JAMA Ophthalmol. 2014;132(9):1076–83. 11. Hu Ying, Shen Jing, Zhang Shuihua, Yang Tao, Huang 20. Grau T, Artemyev NO, Rosenberg T, Dollfus H, Haugen Shangzhi, and Yuan Huiping. A novel splicing mutation OH, Sener EC, et al. Decreased catalytic activity and of the FRMD7 gene in a Chinese family with X-linked altered activation properties of PDE6C mutants associated congenital nystagmus, Molecular Vision 2012;18:87-91. with autosomal recessive achromatopsia. Hum. Mol. 12. Schiaffino MV, d’Addio M, Alloni A, Baschirotto C, Valetti Genet. 2011;20:719–30. C, Cortese K, et al. Ocular albinism: Evidence for a 21. Shah SA, Din SU, Raheem N, Daud S, Mubeen defect in an intracellular signal transduction system. Nat J, Nadeem A, et al. Identification of a novel mutation Genet. 1999;23:108–12. (p.Ile198Thr) in gene TYR in a Pakistani family with 13. Giordano F, Bonetti C, Surace EM, Marigo V, Raposo G. The nonsyndromic oculocutaneous albinism. Clin Exp ocular albinism type 1 (OA1) G-protein-coupled receptor Dermatol. 2014;39(5):646-48. functions with MART-1 at early stages of melanogenesis to 22. Shah SP, Minto H, Jadoon MZ, Bourne RR, Dineen B, control melanosome identity and composition. Hum Mol Gilbert CE, et al. Prevalence and causes of functional Genet. 2009;18:4530–45. low vision and implications for services: the Pakistan 14. Liu J, Jia1 Y, Wang L, Bu J. A previously unidentified National Blindness and Visual Impairment Survey. Invest deletion in G protein‑coupled receptor 143 causing Ophthalmol Vis Sci 2008; 49 (3): 887-93. X‑linked congenital nystagmus in a Chinese family. Indian J 23. Khalil A. Lakho M, Jadoon Z, Mahar PS. Pattern of Ocular Ophthalmol. 2016; 64(11): 813–17 Problems in School going Children of District Lasbela, 15. Ragge NK, Hartley C, Dearlove AM, Walker J, Russell-Eggitt Balochistan. Pak J Ophthalmol. 2012; 28 (4):200-205. I, Harris CM. Familial vestibulocerebellar disorder maps to 24. Shah M, Khan MD. Causes of low vision amongst the chromosome 13q31-q33: a new nystagmus locus. J Med low-vision patients attending the Low-Vision Clinic at Genet 2003; 40:37-41. Khyber Institute of Ophthalmic Medical Sciences (KIOMS), 16. Zelinger L, Cideciyan AV, Kohl S, Schwartz SB, Rosenmann Hayatabad Medical Complex Peshawar, Pakistan. Vis A, Eli D, et al. Genetics and disease expression in the Impair Res. 2004; 6 (2-3): 89-97. CNGA3 form of achromatopsia: steps on the path to gene therapy. Ophthalmology. 2015; 122(5):997-1007. 17. Liang X, Dong F, Li H, Li H, Yang L, Sui R. Novel CNGA3 mutations in Chinese patients with achromatopsia. Br J Ophthalmol. 2015;99(4):571-76 18. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-

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