Mutations in SPATA7 Cause Leber Congenital Amaurosis and Juvenile Retinitis Pigmentosa

Wang, Hui; Hollander, Anneke I. den; Moayedi, Yalda; Abulimiti, Abuduaini; Li, Yumei; Collin, Rob W.J.; Hoyng, Carel B.; López, Irma; Abboud, Emad B.; Al‐Rajhi, Ali A.; Bray, Molly S.; Lewis, Richard A.; Lupski, James R.; Mardon, Graem E.; Koenekoop, Robert K.; Chen, Rui

doi:10.1016/j.ajhg.2009.02.005

Cited by 95 publications

(65 citation statements)

References 32 publications

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“…In spite of this information, the role of Spata genes is not limited to testis development or spermatogenesis. In the mouse, Spata7 transcripts can be detected in multiple layers of the adult mouse retina in addition to spermatocytes [49], and human SPATA genes are implicated in multiple somatic roles. Thus Spata is a misleading symbol, not reflective of tissue or function, and it cannot be assumed that every Spata gene has a role in testis development and spermatogenesis.…”

Section: Discussionmentioning

confidence: 99%

Spata22, a Novel Vertebrate-Specific Gene, Is Required for Meiotic Progress in Mouse Germ Cells1

Palmer

O’Brien

Schimenti

et al. 2012

Biology of Reproduction

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The N-ethyl-N-nitrosourea-induced repro42 mutation, identified by a forward genetics strategy, causes both male and female infertility, with no other apparent phenotypes. Positional cloning led to the discovery of a nonsense mutation in Spata22, a hitherto uncharacterized gene conserved among bony vertebrates. Expression of both transcript and protein is restricted predominantly to germ cells of both sexes. Germ cells of repro42 mutant mice express Spata22 transcript, but not SPATA22 protein. Gametogenesis is profoundly affected by the mutation, and germ cells in repro42 mutant mice do not progress beyond early meiotic prophase, with subsequent germ cell loss in both males and females. The Spata22 gene is essential for one or more key events of early meiotic prophase, as homologous chromosomes of mutant germ cells do not achieve normal synapsis or repair meiotic DNA double-strand breaks. The repro42 mutation thus identifies a novel mammalian germ cell-specific gene required for meiotic progression.

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Section: Discussionmentioning

confidence: 99%

Spata22, a Novel Vertebrate-Specific Gene, Is Required for Meiotic Progress in Mouse Germ Cells1

Palmer

O’Brien

Schimenti

et al. 2012

Biology of Reproduction

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“…LCA represents a group of hereditary retinal diseases characterized and unified by the following constellation of four clinical features-severe and early visual loss, sensory nystagmus, amaurotic pupils, and absent or defective electrical signals on electroretinogram (ERG) (Franceschetti and Dieterle, 1954;Leber, 1869). In most cases, LCA is an autosomal recessive disease associated with mutations that have been already reported in 18 different genes (Banerjee et al, 1998;Chiang et al, 2012;den Hollander et al, 2001den Hollander et al, , 2006den Hollander et al, , 2007Dryja et al, 2001;Estrada-Cuzcano et al, 2011;Falk et al, 2012;Freund et al, 1998;Friedman et al, 2006;Gerber et al, 2001;Jordan et al, 1993;Keen et al, 2003;Koenekoop et al, 2012;Lotery et al, 2001;Marlhens et al, 1997;Morimura et al, 1998;Perrault et al, 1996Perrault et al, , 2004Perrault et al, , 2012Sergouniotis et al, 2011;Sohocki et al, 2000;Stockton et al, 1998;Thompson et al, 2001;Wang et al, 2009;Zeitz et al, 2006). These genes participate in a wide variety of retinal functions including, e.g., phototransduction (GUCY2D), retinoid metabolism (RPE65), or photoreceptor differentiation (CRX).…”

Section: Introductionmentioning

confidence: 97%

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Lustremant

Habeler

Plancheron

et al. 2013

Cellular Reprogramming

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Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA) and to model this type of LCA for drug screening. Fibroblasts from two unrelated clinically identified patients with a yet undetermined gene mutation were reprogrammed to pluripotency by retroviral transduction. These human induced pluripotent stem cells (hiPSCs) were differentiated into neural stem cells (NSCs) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome-wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip(®), comparing LCA-hiPSCs derivatives to controls. A genomic search for alteration in all genes known to be involved in LCA revealed a common polymorphism on the GUCY2D gene, referenced as the LCA type I (OMIM *600179 and #204000), but the causative gene remained unknown. The hiPSCs expressed the key pluripotency factors and formed embryoid bodies in vitro containing cells originating from all three germ layers. They were successfully differentiated into NSC and RPE cells. One gene, NNAT, was upregulated in LCA cell populations, and three genes were downregulated, GSTT1, TRIM61 and ZNF558, with potential correlates for molecular mechanisms of this type of LCA, in particular for protein degradation and oxidative stress. The two LCA patient-specific iPSC lines will contribute to modeling LCA phenotypes and screening candidate drugs.

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“…The following genes are known to be associated with LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, CEP290, IMPDH1, RD3, RDH12, KCNJ13, LRAT and TULP1. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is difficult to estimate the proportion of patients with mutations in the different genes, as some, such as IMPDH1 (LCA11) is considered to be rare, other, as CEP290 accounts for almost 20%, and for some such as TULP1 and LRAT the number is uncertain. One of the most studied LCA genes is CRB1 at 1q31q32.1, which consists of 12 exons and encodes a protein Crumbs homologue that participates in determination and maintenance of photoreceptor architecture.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

et al. 2013

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This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C4T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T4C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773 þ 3A4G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

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Mutations in SPATA7 Cause Leber Congenital Amaurosis and Juvenile Retinitis Pigmentosa

Cited by 95 publications

References 32 publications

Spata22, a Novel Vertebrate-Specific Gene, Is Required for Meiotic Progress in Mouse Germ Cells1

Spata22, a Novel Vertebrate-Specific Gene, Is Required for Meiotic Progress in Mouse Germ Cells1

Human Induced Pluripotent Stem Cells As a Tool to Model a Form of Leber Congenital Amaurosis

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

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