Congenital Fibrosis of the Extraocular Muscles Type 2, an Inherited Exotropic Strabismus Fixus, Maps to Distal 11q13

Wang, S.M.; Zwaan, Johan; Mullaney, Paul; Jabak, Monzer; Al-Awad, Abdulaziz; Beggs, Alan H.; Engle, Elizabeth C.

doi:10.1086/301980

Cited by 90 publications

(52 citation statements)

References 20 publications

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“…fz encodes a seven-transmembrane helix containing protein necessary for binding Wnt ligands in the noncanonical Wnt signaling pathway (82) and has 10 human orthologs encoding frizzled class receptors, of which FZD4 is associated with exudative vitreoretinopathy (83). hbn encodes a transcription factor and has four human orthologs, of which PHOX2A has been associated with congenital fibrosis of extraocular muscles, a disorder that affects the muscles that control eye movement and position of the eyes (84,85). ktub has three human orthologs, of which TUB is associated with retinal dystrophy and TULP1 is associated with retinitis pigmentosa (86,87) and Leber congenital amaurosis (early-onset retinal dystrophy) (88, 89).…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of natural variation in visual senescence in Drosophila

Carbone

Yamamoto

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.aging | behavioral genetics | DGRP GWA analysis | phototaxis | xQTL mapping

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Section: Discussionmentioning

confidence: 99%

Genetic architecture of natural variation in visual senescence in Drosophila

Carbone

Yamamoto

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…2e). To determine the genetic cause of this CCDD, we conducted a genome-wide linkage screen and mapped CFEOM2 to chromosome 11q13, referred to as the FEOM2 locus (26). We constructed a physical map across the FEOM2 region and screened candidate genes within it (27).…”

Section: Cfeom2mentioning

confidence: 99%

The Genetic Basis of Complex Strabismus

Engle

2006

Pediatr Res

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Members of my research laboratory combine clinical, genetic, and molecular biologic approaches to the study of congenital strabismus. Strabismus, which is misalignment of the eyes, affects 2-4% of the population and causes loss of binocular vision and amblyopia (vision loss in a structurally normal eye). The cause of strabismus when it occurs in the absence of structural brain abnormalities is generally unknown. In the last decade, we have focused our research studies on understanding the genetic etiology of a series of complex strabismus syndromes in which eye movement in at least one direction is limited or paralyzed. We are discovering that these disorders result from mutations in genes necessary for the normal development and connectivity of brainstem ocular motoneurons, including PHOX2A, SALL4, KIF21A, ROBO3, and HOXA1, and we now refer to these syndromes as the "congenital cranial dysinnervation disorders," or CCDD. (Pediatr Res 59: 343-348, 2006)

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“…We have identified this recessive disorder in consanguineous pedigrees, mapped it to the FEOM2 locus on 11q13, 9 and shown that it results from homozygous mutations in PHOX2A (ARIX). 10,11 PHOX2A encodes a homeodomain transcription factor essential to the development of the oculomotor and trochlear motoneurons in mice and zebrafish.…”

mentioning

confidence: 99%

Identification ofKIF21AMutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

Yamada

Chan

Andrews

et al. 2004

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G3 A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C3 T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A.CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype. (Invest Ophthalmol Vis Sci.

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Congenital Fibrosis of the Extraocular Muscles Type 2, an Inherited Exotropic Strabismus Fixus, Maps to Distal 11q13

Cited by 90 publications

References 20 publications

Genetic architecture of natural variation in visual senescence in Drosophila

Genetic architecture of natural variation in visual senescence in Drosophila

The Genetic Basis of Complex Strabismus

Identification ofKIF21AMutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3)

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