Microphthalmia, Anophthalmia, and Coloboma and Associated Ocular and Systemic Features

Skalicky, Simon E.; White, Andrew; Grigg, John; Martin, Frank; Smith, Jeremy B.; Jones, Michael W. M.; Donaldson, Craig; Smith, James E.; Flaherty, Maree; Jamieson, Robyn V

doi:10.1001/jamaophthalmol.2013.5305

Cited by 63 publications

(60 citation statements)

References 56 publications

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“…Although coloboma is a common association with microphthalmia, this does not necessarily mean that coloboma is a non-specific outcome of microphthalmia. A recent study of 141 patients with microphthalmia, anophthalmia and coloboma phenotypes revealed a similar number of microphthalmic cases without coloboma (24%) to those with optic fissure closure defects and normal globe size (23%) (65). None of the patients in the present study were clinically diagnosed as microphthalmic.…”

Section: Discussionmentioning

confidence: 95%

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Kelberman

Islam

Lakowski³

et al. 2014

Human Molecular Genetics

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Ocular coloboma is a congenital defect resulting from failure of normal closure of the optic fissure during embryonic eye development. This birth defect causes childhood blindness worldwide, yet the genetic etiology is poorly understood. Here, we identified a novel homozygous mutation in the SALL2 gene in members of a consanguineous family affected with non-syndromic ocular coloboma variably affecting the iris and retina. This mutation, c.85G>T, introduces a premature termination codon (p.Glu29*) predicted to truncate the SALL2 protein so that it lacks three clusters of zinc-finger motifs that are essential for DNA-binding activity. This discovery identifies SALL2 as the third member of the Drosophila homeotic Spalt-like family of developmental transcription factor genes implicated in human disease. SALL2 is expressed in the developing human retina at the time of, and subsequent to, optic fissure closure. Analysis of Sall2-deficient mouse embryos revealed delayed apposition of the optic fissure margins and the persistence of an anterior retinal coloboma phenotype after birth. Sall2-deficient embryos displayed correct posterior closure toward the optic nerve head, and upon contact of the fissure margins, dissolution of the basal lamina occurred and PAX2, known to be critical for this process, was expressed normally. Anterior closure was disrupted with the fissure margins failing to meet, or in some cases misaligning leading to a retinal lesion. These observations demonstrate, for the first time, a role for SALL2 in eye morphogenesis and that loss of function of the gene causes ocular coloboma in humans and mice.

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Section: Discussionmentioning

confidence: 95%

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Kelberman

Islam

Lakowski³

et al. 2014

Human Molecular Genetics

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“…Coloboma is a congenital segmental ocular defect which can affect one or more structures of the eye; typical coloboma results in an inferior deficiency of iris, chorioretinal, and/or optic nerve tissue [1–3]. Ocular coloboma is believed to result from failure of normal closure of the optic fissure during embryonic eye development, termed optic fissure closure defect (OFCD) [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…Coloboma can occur as an isolated anomaly (simple coloboma) but in most cases it is associated with additional ocular defects, including microphthalmia, cataract, retinal detachment, and ocular motility disorders [1–4]. Microcornea, a reduction in the diameter of the cornea, is common in colobomatous eyes and can be associated with normal or even increased (macrophthalmic) axial length [2,3,5]. Additional systemic anomalies are present in a large proportion of patients with OFCDs including brain, skeletal, cardiac, or urogenital anomalies [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Mutations in MAB21L2 Result in Ocular Coloboma, Microcornea and Cataracts

Kariminejad²,

et al. 2015

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Ocular coloboma results from abnormal embryonic development and is often associated with additional ocular and systemic features. Coloboma is a highly heterogeneous disorder with many cases remaining unexplained. Whole exome sequencing from two cousins affected with dominant coloboma with microcornea, cataracts, and skeletal dysplasia identified a novel heterozygous allele in MAB21L2, c.151 C>G, p.(Arg51Gly); the mutation was present in all five family members with the disease and appeared de novo in the first affected generation of the three-generational pedigree. MAB21L2 encodes a protein similar to C. elegans mab-21 cell fate-determining factor; the molecular function of MAB21L2 is largely unknown. To further evaluate the role of MAB21L2, zebrafish mutants carrying a p.(Gln48Serfs*5) frameshift truncation (mab21l2Q48Sfs*5) and a p.(Arg51_Phe52del) in-frame deletion (mab21l2R51_F52del) were developed with TALEN technology. Homozygous zebrafish embryos from both lines developed variable lens and coloboma phenotypes: mab21l2Q48Sfs*5 embryos demonstrated severe lens and retinal defects with complete lethality while mab21l2R51_F52del mutants displayed a milder lens phenotype and severe coloboma with a small number of fish surviving to adulthood. Protein studies showed decreased stability for the human p.(Arg51Gly) and zebrafish p.(Arg51_Phe52del) mutant proteins and predicted a complete loss-of-function for the zebrafish p.(Gln48Serfs*5) frameshift truncation. Additionally, in contrast to wild-type human MAB21L2 transcript, mutant p.(Arg51Gly) mRNA failed to efficiently rescue the ocular phenotype when injected into mab21l2Q48Sfs*5 embryos, suggesting this allele is functionally deficient. Histology, immunohistochemistry, and in situ hybridization experiments identified retinal invagination defects, an increase in cell death, abnormal proliferation patterns, and altered expression of several ocular markers in the mab21l2 mutants. These findings support the identification of MAB21L2 as a novel factor involved in human coloboma and highlight the power of genome editing manipulation in model organisms for analysis of the effects of whole exome variation in humans.

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“…A/M can be isolated or associated with other anomalies. Anophthalmia rarely occurs in isolation, with its birth prevalence ranging from 0.6 to 4.2 per 100,000 births (Skalicky et al , 2013). …”

Section: Introductionmentioning

confidence: 99%

Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family

Liao

2017

Genet. Mol. Biol.

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Anophthalmia is a rare eye development anomaly resulting in absent ocular globes or tissue in the orbit since birth. Here, we investigated a newborn with bilateral anophthalmia in a Chinese family. Exome sequencing revealed that compound heterozygous mutations c.287G > A (p.(Arg96His)) and c.709G > A (p.(Gly237Arg)) of the ALDH1A3 gene were present in the affected newborn. Both mutations were absent in all of the searched databases, including 10,000 in-house Chinese exome sequences, and these mutations were confirmed as having been transmitted from the parents. Comparative amino acid sequence analysis across distantly related species revealed that the residues at positions 96 and 234 were evolutionarily highly conserved. In silico analysis predicted these changes to be damaging, and in vitro expression analysis revealed that the mutated alleles were associated with decreased protein production and impaired tetrameric protein formation. This study firstly reported that compound heterozygous mutations of the ALDH1A3 gene can result in anophthalmia in humans, thus highlighting those heterozygous mutations in ALDH1A3 should be considered for molecular screening in anophthalmia, particularly in cases from families without consanguineous relationships.

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Microphthalmia, Anophthalmia, and Coloboma and Associated Ocular and Systemic Features

Cited by 63 publications

References 56 publications

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Mutation of SALL2 causes recessive ocular coloboma in humans and mice

Mutations in MAB21L2 Result in Ocular Coloboma, Microcornea and Cataracts

Novel compound heterozygous mutations of ALDH1A3 contribute to anophthalmia in a non-consanguineous Chinese family

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