Sullivan Lori S, Bowne Sara J, Koboldt Daniel C, Cadena Elizabeth L, Heckenlively John R, Branham Kari E, Wheaton Dianna H, Jones Kaylie D, Ruiz Richard S, Pennesi Mark E, Yang Paul, Davis-Boozer David, Northrup Hope, Gurevich Vsevold V, Chen Rui, Xu Mingchu, Li Yumei, Birch David G, Daiger Stephen P
Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States.
Nationwide Children's Hospital, Columbus, Ohio, United States.
Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2774-2784. doi: 10.1167/iovs.16-21341.
To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.
Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.
Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.
This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
在一组已知常染色体显性遗传性视网膜色素变性（adRP）基因无突变的家族中确定adRP的病因，并对SAG基因中一个新的显性错义突变进行特征描述。
患者接受眼科检查，并使用靶向捕获和全外显子组新一代测序技术筛查突变。通过桑格测序进行确认和额外筛查。利用短串联重复序列和单核苷酸变异多态性确定与突变共分离的单倍型。通过对家庭成员的访谈建立家系。
在300个adRP家族队列中的8个家族以及另外4个家族中，发现SAG基因存在一个新的杂合突变，即c.440G>T；p.Cys147Phe。患者表现出视网膜色素变性症状，且均未表现出Oguchi病的特征性症状。所有家族均为西班牙裔，大多数在得克萨斯州或加利福尼亚州被确诊。在所有家族中鉴定出一个包含SAG突变的单倍型。该突变显著改变了一个保守氨基酸，在全球数据库中极为罕见，在4000多个西班牙裔对照外显子组中未发现。基于牛视紫红质抑制蛋白-1晶体结构的分子建模预测蛋白质错误折叠/不稳定。
这是在SAG基因中鉴定出的首个显性作用突变，是一个可能起源于几个世纪前墨西哥的奠基者突变。该表型明确为adRP，与先前报道的隐性无义突变表型（即Oguchi病和隐性RP）不同。该突变在adRP队列的300个家族中占3%，在该队列的西班牙裔家族中占36%。
