Leber Congenital Amaurosis 17

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

RPGRIP1, CRX, CRB1, NMNAT1, RPE65, AIPL1, CEP290, IQCB1, LCA5, SPATA7, TULP1, KCNJ13, LRAT, IMPDH1, RD3, GUCY2D, RDH12, USP45, GDF6, MERTK, IFT140, PCYT1A, MPP5, ABCA4, CLUAP1, USH2A, SLC38A8, CDHR1, GRM6, RP2, AHI1, PDE6A, CNGB3, GIGYF2, ZFYVE26, NR2E3, RGS9, CRB2, LCA10, OTX2, CLTA, PTPRC, MYO7A, CNGA3, CCT2, GUCA1A, PRPH2, IMPG1, CABP4, GUCY2F, SLC7A14, GUCA1B, LPCAT1, HSD17B6, ENO2, CNTLN, PSMD13, PRPH, GUCY2EP, BCL2, MIR204, EGF, SP4, RPGR, NUB1, ADH7, NRL, TUB, ND4, FST, SLC19A2, PRPF8, PNPLA6, CILK1, NINL, SERPINF1, RPGRIP1L, MEF2C, TAP2, MEF2A, ELOVL4, IMPG2, PDE6B

Drugs

9-cis-Retinyl acetate, Adeno-associated viral vector serotype 8 containing the human AIPL1 gene, Adeno-associated viral vector serotype 8 containing the human GUCY2D gene

9-cis-Retinyl acetate, Adeno-associated viral vector serotype 8 containing the human AIPL1 gene, Adeno-associated viral vector serotype 8 containing the human GUCY2D gene, Adeno-associated virus serotype 8 containing the human RdCVF sequence and the human RdCVFL sequence, Adenovirus associated viral vector serotype 4 containing the human RPE65 gene, Adenovirus associated viral vector serotype 5 containing the human RPE65 gene, Adenovirus-associated viral vector serotype 2 containing the human RPE65 gene (AAV2-hRPE65v2 ), Antisense oligonucleotide complementary to the exonic splicer enhancer sequence at intron 26 of the centrosomal protein 290 pre-mRNA, Combination of three adeno-associated viral vectors of serotype 8 containing the 5'-, the body- and the 3'- coding sequences of human CEP290 fused to inteins, Recombinant adeno-associated viral vector serotype 5 encoding Staphylococcus aureus Cas9 endonuclease and two guide RNAs complementary to two regions of intron 26 of the CEP290 gene

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A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-17 (LCA17) is caused by compound heterozygous mutation in the GDF6 gene (601147) on chromosome 8q22.

For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis (LCA), see LCA1 (204000).

Clinical Features

Asai-Coakwell et al. (2013) studied a female LCA patient with compound heterozygous mutations in the GDF6 gene who had vision limited to detection of hand motions, with an extinguished electroretinogram (ERG) typical of the LCA phenotype. She did not have other ocular or systemic phenotypes, but the authors noted that she had not undergone radiologic imaging to detect milder GDF6-induced skeletal disease. Evaluation of her clinically unaffected mother revealed a delayed rod b-wave implicit time on ERG; similarly, her apparently unaffected father showed reduced b-wave amplitude.

Molecular Genetics

Asai-Coakwell et al. (2013) analyzed the GDF6 gene in 279 DNA samples from patients diagnosed with Leber congenital amaurosis or juvenile retinitis pigmentosa (JRP) who were negative for mutation in known causative genes, and identified compound heterozygosity for 2 missense mutations in 1 female LCA proband: A249E (601147.0001) and D57H (601147.0008). The A249E mutation had previously been identified in a family with Klippel-Feil syndrome (118100), in 1 proband with isolated microphthalmia (MCOP4; 613094), and in a patient with coloboma and postaxial polydactyly without vertebral defects. Heterozygosity for GDF6 missense mutations was identified in 3 probands from the LCA/JRP cohort: A249E, A199T (601147.0007), and E292D (601147.0009). Asai-Coakwell et al. (2013) hypothesized that a second variant in the TGF-beta (see 190180) pathway was present in the probands with a heterozygous GDF6 mutation, but exome sequencing yielded incomplete coverage across open-reading frames of BMP (see 112261) ligands, preventing identification of known heterozygous mutations.

Animal Model

Asai-Coakwell et al. (2013) generated mice with a targeted deletion of Gdf6 exon 2 and observed that heterozygotes exhibited abnormal electroretinograms with up to 66% decreases in the bipolar cell-driven b-wave and 54% decreases in the photoreceptor-mediated a-wave amplitudes, as well as 3 to 27% reduced photopic flicker fusion, findings compatible with a role for GDF6 in retinal function. Examination of adult zebrafish homozygous for a Gdf6 S55X mutation showed microphthalmia and misshapen irides. Histologic analysis of homozygous mutants at 2 weeks of age demonstrated profound alterations to the morphology of individual photoreceptor subtypes, including red/green and UV cones. Actin and nuclear staining at later timepoints revealed loss of normal retinal lamination, and immunohistochemistry showed disorganization of Muller glial cells. Cone photoreceptors in homozygous mutant adult zebrafish were consistently dysmorphic and reduced in abundance. In addition, significantly increased retinal apoptosis was observed in Gdf6 mutant mice and zebrafish compared to wildtype animals; treatment of mutant zebrafish embryos with the antiapoptotic compound P7C3 rescued the retinal apoptosis without evidence of toxicity. Asai-Coakwell et al. (2013) stated that this was the first evidence of perturbed TGF-beta (see 190180) signaling in retinal disease.