A New Locus for Autosomal Dominant Cataract on Chromosome 19: Linkage Analyses and Screening of Candidate Genes

Bateman, J. Bronwyn; Richter, L.; Flodman, Pamela; Burch, D.; Brown, Sandra; Penrose, Philip; Paul, Otis; Geyer, David D.; Brooks, David G.; Spence, M. Anne

doi:10.1167/iovs.05-1035

Cited by 8 publications

(8 citation statements)

References 80 publications

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“…41 Sequencing of several candidate genes within this region (MIP, LIM2, SIX5, and FTL, but not SIPA1L3) in the affected family members failed to detect a sequence variant. However, in this family the cataract showed autosomal dominant inheritance, later onset and a cortical localization.…”

Section: Discussionmentioning

confidence: 93%

“…However, in this family the cataract showed autosomal dominant inheritance, later onset and a cortical localization. 41 Other putative cataract genes in the previously mapped region for autosomal dominant cataract include PRX, EML2, SPINT2, and PVRL2. 40 The above candidate genes were covered in our exome sequence data and included for further data analysis but did not yield any interesting candidate variants.…”

Section: Discussionmentioning

confidence: 99%

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SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

et al. 2015

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Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

et al. 2015

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“…Interestingly, defects in the neural retina do not appear in these mice, which then begs the question of what role Six5 plays in the retina and whether its function is redundant with the other SIX proteins. A connection between human Six5 and DM-associated cataracts has proved somewhat tenuous as sequencing of the Six5 locus in several patients suffering from DM has failed to identify any lesions within the coding regions or 5′ and 3′ untranslated regions [117]. However, the regulatory regions of hSix5 were not analyzed, and it is quite possible that a mutation with a regulatory sequence may be responsible for the ocular defects in DM patients.…”

Section: Six Proteins In Retinal Developmentmentioning

confidence: 99%

The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease

Kumar

2008

Cell. Mol. Life Sci.

223

222

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The sine oculis homeobox (SIX) protein family is a group of evolutionarily conserved transcription factors that are found in diverse organisms that range from flatworms to humans. These factors are expressed within, and play pivotal developmental roles in, cell populations that give rise to the head, retina, ear, nose, brain, kidney, muscle and gonads. Mutations within the fly and mammalian versions of these genes have adverse consequences on the development of these organs/tissues. Several SIX proteins have been shown to directly influence the cell cycle and are present at elevated levels during tumorigenesis and within several cancers. This review aims to highlight aspects of (1) the evolutionary history of the SIX family; (2) the structural differences and similarities amongst the different SIX proteins; (3) the role that these genes play in retinal development; and (4) the influence that these proteins have on cell proliferation and growth. KeywordsSine oculis; optix; DSix4; Drosophila; SIX; mammals; retina; gonad; mesoderm SIX proteins: A family historyMutations within the founding member of the sine oculis homeobox (SIX) family, sine oculis (so), were first identified and characterized in the fruit fly, Drosophila melanogaster at a time when a growing number of mutants affecting the structure, size and pigmentation of the eye were being recovered [1]. Mutations in so proved to be particularly interesting as loss-offunction mutants not only had dramatic effects on the compound eye but also, in fact, adversely affected the entire visual system [2][3][4][5]. Subsequent molecular efforts identified two additional SIX family members, optix and DSix4 in flies [6,7]. optix, like so, is expressed and functions in the developing eye, although its role in the retina appears to be distinct from that of so [7][8][9]. DSix4, on the other hand, plays no role in the eye but instead functions in several mesoderm derivatives including a subset of somatic muscles, the somatic cells of the gonad and the fat body [10,11]. The three SIX genes that are found in Drosophila are thought to have arisen through the duplication of an ancestral SIX gene, an event that occurred prior to the evolution of the Bilateria. Homologs of the so, optix and DSix4 proteins have been identified in a wide range of organisms throughout the animal kingdom. A comparison of gene structures and sequence has led to the creation of three subclasses of SIX proteins: each class contains one of the fly genes and their orthologs ( Fig. 1) [6]. The remarkable demonstration that Pax6 (ey in flies, Sey in mouse, Pax6 in humans) universally governs retinal development across the animal kingdom was a strong impetus to find vertebrate orthologs of the other genes involved in fly retinal specification [12][13][14]. In the immediate years after cloning so from the fruit fly, homologs were quickly identified in a number of vertebrate systems including medaka fish, chickens, frogs, zebrafish, mice and humans [15][16][17][18][19][20][21][22][23][24][25][26][27][...

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“…In zebrafish, Six1 promotes the formation of hair cells by increasing their proliferation, while inhibiting neurogenesis by inducing apoptosis (Bricaud and Collazo, 2006). Finally, Six5 mutations lead to cataract formation in the lens (Klesert, et al, 2000;Sarkar, et al, 2000;Bateman, et al, 2006) and are associated with BOR syndrome in humans (Hoskins, et al, 2007).…”

Section: Six and Eya Genes In Sensory Organ Formationmentioning

confidence: 99%

The preplacodal region: an ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

Streit¹

2007

Int. J. Dev. Biol.

172

187

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The otic primordium belongs to a group of related structures, the sensory placodes that contribute to the paired sense organs -ear, eye and olfactory epithelium -and to the distal parts of the cranial sensory ganglia. Recent evidence suggests that despite their diversity, all placodes share a common developmental origin and a common molecular mechanism which initiates their formation. At the base of placode induction lies the specification of a unique "placode field", termed the preplacodal region and acquisition of this "preplacodal state" is required for ectodermal cells to undergo otic development. Here I review the molecular mechanisms that sequentially subdivide the ectoderm to give rise to the placode territory.

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A New Locus for Autosomal Dominant Cataract on Chromosome 19: Linkage Analyses and Screening of Candidate Genes

Abstract: The mutated gene in ADC4 probably represents a new, not yet identified locus on chromosome 19. In one phakic member, the cortical cataracts were punctate and vacuolated.

Cited by 8 publications

References 80 publications

SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

The sine oculis homeobox (SIX) family of transcription factors as regulators of development and disease

The preplacodal region: an ectodermal domain with multipotential progenitors that contribute to sense organs and cranial sensory ganglia

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