Cone dystrophy and ectopic synaptogenesis in a Cacna1f loss of function model of congenital stationary night blindness (CSNB2A)

Inherited retinal dystrophies (IRDs) are characterized by high clinical and genetic heterogeneity. A precise characterization is desirable for diagnosis and has impact on prognosis, patient counseling, and potential therapeutic options. Here, we demonstrate the effectiveness of the combination of in-depth retinal phenotyping and molecular genetic testing in complex pedigrees with different IRDs. Four affected Caucasians and two unaffected relatives were characterized including multimodal retinal imaging, functional testing, and targeted next-generation sequencing. A considerable intrafamilial phenotypic and genotypic heterogeneity was identified. While the parents of the index family presented with rod-cone dystrophy and ABCA4-related retinopathy, their two sons revealed characteristics in the spectrum of incomplete congenital stationary night blindness and ocular albinism, respectively. Molecular testing revealed previously described variants in RHO, ABCA4, and MITF as well as a novel variant in CACNA1F. Identified variants were verified by intrafamilial co-segregation, bioinformatic annotations, and in silico analysis. The coexistence of four independent IRDs caused by distinct mutations and inheritance modes in one pedigree is demonstrated. These findings highlight the complexity of IRDs and underscore the need for the combination of extensive molecular genetic testing and clinical characterization. In addition, a novel variant in the CACNA1F gene is reported associated with incomplete congenital stationary night blindness.

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A Novel Heterozygous Missense Mutation in GNAT1 Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness

BioMed Research International ◽

10.1155/2018/7694801 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Christina Zeitz ◽

Cécile Méjécase ◽

Mathilde Stévenard ◽

Christelle Michiels ◽

Isabelle Audo ◽

...

Keyword(s):

Binding Site ◽

Night Blindness ◽

Autosomal Dominant ◽

Protein Localization ◽

Cone Dystrophy ◽

Congenital Stationary Night Blindness ◽

Gtp Binding ◽

Novel Variant ◽

Localization Signal ◽

Phototransduction Cascade

Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in GNAT1 coding for the α-subunit of transducin, cosegregating with the phenotype. Domain predictions and 3D-modelling suggest that the variant does not affect the GTP-binding site as other GNAT1 adCSNB mutations do. It affects a predicted nuclear localization signal and a part of the first α-helix, which is distant from the GTP-binding site. The subcellular protein localization of this and other mutant GNAT1 proteins implicated in CSNB are unaltered in mammalian GNAT1 overexpressing cells. Our findings add a third GNAT1 mutation causing adCSNB and suggest that different pathogenic mechanisms may cause this condition.

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