Rhodes Hannah L, Yarram-Smith Laura, Rice Sarah J, Tabaksert Ayla, Edwards Noel, Hartley Alice, Woodward Mark N, Smithson Sarah L, Tomson Charles, Welsh Gavin I, Williams Margaret, Thwaites David T, Sayer John A, Coward Richard J M
Academic and Children's Renal Unit, School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
Bristol Genetics Laboratory-Pathology Sciences and.
Clin J Am Soc Nephrol. 2015 Jul 7;10(7):1235-45. doi: 10.2215/CJN.10981114. Epub 2015 May 11.
Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b(0,+), the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.
In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having ≥10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotype-phenotype association was detected in this cohort.
Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at ≥40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.
胱氨酸尿症是一种罕见的遗传性肾结石疾病。氨基酸交换体系统b(0,+)的突变主要导致该疾病，其两个亚基由SLC3A1和SLC7A9编码。这项研究分析了英国队列中胱氨酸尿症的流行病学以及这两个基因的突变对疾病严重程度的影响。
设计、地点、参与者及测量方法：2012年至2014年在英国东北部和西南部对现患患者进行了研究。定义了临床表型，并对SLC3A1和SLC7A9进行了基因分析，结合了桑格测序和多重连接探针依赖扩增技术。
共研究了76例患者（42例男性和34例女性）。所有受试者均确诊为胱氨酸结石。首次发病（首次结石发作）的中位年龄为24岁，但21%的患者在40岁以后发病。患者的临床病程各不相同，37%的患者有≥10次结石发作；70%的患者有慢性肾脏病证据，9%的患者因胱氨酸尿症及其并发症发展为终末期肾病。胱氨酸尿症患者接受了多种不同的治疗，没有明显的治疗共识。值得注意的是，20%的患者有鹿角形结石，其中80%的患者伴有肾功能受损。基因分析显示，SLC3A1（n = 27）或SLC7A9（n = 20）存在双等位基因突变；22例患者仅检测到一个突变等位基因（5例患者为SLC3A1，17例患者为SLC7A9）。总共鉴定出37种不同的突变变异等位基因，包括1处新突变；22%的突变由大片段基因重排引起。该队列中未检测到基因型与表型的关联。
英国的胱氨酸尿症患者通常在40岁及以上出现非典型的鹿角形结石，且常出现严重的肾功能损害。临床病程与基因型无关联。需要对旨在减轻结石负担的治疗方法进行合理化和开发，以优化患者护理。
