Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness

GNB3中的双等位基因突变导致先天性静止性夜盲常染色体隐性遗传的独特形式

【摘要学习】

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features.

Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein

CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement.

Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). （一个家系进行全外显子测序，发现与CSNB相关的基因突变为阴性，发现鸟嘌呤核苷酸结合蛋白亚基β-3基因(GNB3)存在双等位突变）Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339*]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339*]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the b subunit of G protein heterotrimer (Gabg) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signalin

【introduction 学习】

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders that follow autosomal-dominant, autosomal-recessive, or X-linked patterns of inheritance.1CSNB results from defects in visual signal transduction either within rod photoreceptors or in rod and cone bipolar pathways.

Full-fieldelectroretinogram(ERG)testing is an essential tool to diagnose CSNB and helps to localize the functional deficit to photoreceptor or bipolar-cell signaling. In brief, a bright flash(3.0and10.0cd.s.m?2[candela second per square meter] as defined by the International Society for Clinical Electrophysiology of Vision [ISCEV]) under dark-adapted (DA) conditions normally elicits an initial negative wave (a-wave) that reflects phototransduction- related photoreceptor hyperpolarization predominated by the rods; the subsequent positive wave (b-wave) mostly reflects ON bipolar cell depolarization. Under light-adapted (LA) conditions, a standard flash (3.0 cd.s.m?2) elicits an initial a-wave generated by cone photoreceptor hyperpolarization with an additional contribution from cone OFF bipolar cells; the subsequent b-wave is generated from within ON and OFF bipolar cells. The LA 30 Hz stimuli (3.0 cd.s.m?2) lead to a sinusoidal response generated in the inner retina that is driven by cones.3–7

AIM

METHOS

【在家系中的WES分析中使用的过滤步骤】【我要学习的地方】

KEY RESULTS

C）GNB3在脊椎动物和GNB同源物中跨越一系列生物分类群的保护图； Lys57和Trp339是最保守的氨基酸残基。 

（D）Conservation of amino-acid residues across GNB paralogs

（E和F）用Phyre2【？？这是个软件？我要去学习一下；刚查了一下是一个蛋白质解构预测的网站】生成的GNB3的同源性模型。标记了基于GNB1的1TBG结构（链A [PDB：1TBG]）和突变残基的GNB3同源性模型的结构。 

（G和H）GNB3的表面示意图说明了蛋白在Trp339处的终止将如何造成结构的显着损失和正常掩埋残基的暴露。 Trp表面（绿色）显示在（G）中，而去除Trp339和Asn340（黄色星号突出显示）的结构损失显示在（H）中。 

（I）Ser67的位置示意图，显示了与Ala322和Asp323的两个潜在氢键； p.Ser67Phe突变会破坏这两种相互作用。 Trp339位于b桶结构的同一区域，可能表明GNB3的这一区域具有重要的生物学作用。 

（J和K）Lys57（p.Lys57del）的丢失会导致Gb5：RGS相互作用的破坏。 GNB3显示为蓝色，RGS显示为绿色，Lys57显​​示为红色棒，结合天冬氨酸显示为橙色棒。

CONCLUSION

1.This paper identifies an unusual and unique stationary retinal disorder with dual anomaly in visual processing associated with biallelic mutations in GNB3

2.Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.

COMMENTS

十分的文章和五分的差别，我觉得就是他对突变蛋白的结构进行了预测