OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

PurposeNephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery. Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.MethodsExome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.ResultsExome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or NC disease in an autosomal dominant inheritance pattern within a multigenerational family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron. In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger, pendrin, which also regulates transepithelial calcium transport in cortical connecting tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico prediction scores, and extreme rarity in exome population databases suggested that the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium controls (χ² = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca²⁺ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca²⁺ uptake, demonstrating loss of function.ConclusionRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.     

Charcot—Marie—Tooth病的遗传,临床和电生理观察（附20例临床分析）

本文报道 ２０例 Ｃｈａｒｃｏｔ－Ｍａｒｉｅ－Ｔｏｏｔｈ病的遗传、临床和电生理资料。其中男 １６例,女 ４例,平均发病年龄为２６．７５岁。发现４例显性遗传,３例隐性遗传,１０例散发,３例遗传情况不详。主要症状有高弓足、垂足、鹤腿和腱反射消失;上肢前臂有肌萎缩者占１／４。所有病人电生理检查均有失神经现象,特别是ＭＣＶ有明显减慢。且发现ＭＣＶ的减慢和临床严重程度无相关联系。     

A genetic study of idiopathic focal dystonias

The inheritance of focal dystonias was investigated in 43 families containing 43 index cases with torticollis (n = 21), blepharospasm (n = 18) and writer's cramp (n = 4). They generated a potential population of 235 first-degree relatives, and 168 out of 179 living first-degree relatives were examined. Ten relatives with dystonia were identified in ten families. Another two parents from two of the same group of ten families were affected according to the family history. The majority of the secondary cases (six patients, five siblings, and one child) were not aware of any dystonia. The tendency for affected relatives to have the same type of dystonia as index patients was observed only for torticollis. Overall, 23% of index patients had relatives with dystonia. Segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrante underlying focal dystonia.     

谷子种子经高空气球搭载后的遗传变异研究

目的 选育出高产、蛋白质和用脂肪含量高的谷子品（系）种。方法 利用高空气球搭载谷子的干种子,在高空飘游８ｈ后回收种植,对其植物学特性及进行分析研究。结果 种子发芽率比对照低５．２％,发芽热比对照高２１．１％。ＳＰ１代植株高度比对照低６．８ｃｍ,旗叶面积比对照高２５％,穗重比对照高１５．９％;ＳＰ３代大穗型株系性状相对稳定,其中ＳＰ３－２的种子蛋白质和脂肪含量均高于对照经高空气球搭载后的ＳＰＥ－３５     

Apolipoprotein E polymorphisms and the risk of nonlesional temporal lobe epilepsy

PURPOSE: To evaluate whether the inheritance of the apolipoprotein E (ApoE) epsilon4 allele is a risk factor for nonlesional temporal lobe epilepsy (TLE), and to determine whether the newly described -491 A/T ApoE polymorphism may independently affect the risk of nonlesional TLE. METHODS: The study group consisted of 63 patients (35 women and 28 men; age at onset of epilepsy, 30.6 +/- 19.6 years; mean (+/-SD). All of them had received a diagnosis of nonlesional TLE after a detailed clinical, electroencephalographic, and brain magnetic resonance investigation. The ApoE polymorphisms were determined from blood samples by standard methods. The molecular study also was performed in 220 age- and sex-matched normal individuals. RESULTS: There were no differences between TLE patients and controls in either allelic or genotypic frequencies of the ApoE and -491A/T polymorphisms. Moreover, no effect of ApoE or -491A/T polymorphisms was found on the age at onset and severity of epilepsy. CONCLUSIONS: The allelic and genotypic frequencies of ApoE polymorphisms in Italian patients with nonlesional TLE are comparable to control values, indicating that ApoE polymorphisms are not a significant genetic risk factor for the occurrence of nonlesional TLE.     

Avoidance behavior in rats selectively bred for differential alcohol sensitivity

Most affected (MA) and least affected (LA) rats, bred for extremes in motor impairment following an alcohol challenge, differed in their performance on two active avoidance tasks. In two-way shuttle avoidance, the MA line performed significantly better than the LA group, both in terms of response latencies and percent avoidances. The inferior performance of the LA line persisted across the 15 days of testing, and appeared to reflect an difference in asymptotic performance levels. In one-way avoidance, the MA line showed significantly better acquisition than the LA group; however, this difference dissipated across the 3 days of training. When tested following alcohol administration in either the one-or two-way avoidance paradigm, the MA rats showed a greater performance deficit than LA animals. These data were interpreted as indicating the generality of alcoholrelated line differences to a situation motivated by aversive consequences. Moreover, the line difference in avoidance acquisition represents one of the few non-drug-related phenotypic differences that have been found in these lines. In previous generations, disparate base rates of wheel running have been reported, and the data presented here confirm and extend this finding.     

Factors involved in the differential response to ethanol,barbital and pentobarbital in rats selectively bred for ethanol sensitivity

Two lines of rats, least affected (LA) and most affected (MA), had been selectively bred for their differential sensitivity to ethanol. Both males and females of the LA strain were observed to be less sensitive than their MA counterparts to the acute hypnotic and motor-impairing effects of ethanol. However, a lower ethanol metabolic rate of the MA males suggests that both CNS and metabolic factors contribute to their enhanced sensitivity to ethanol. By contrast, no differences were observed between the LA and MA males with respect to the hypnotic and subhypnotic effects of pentobarbital or to the clearance of this drug. MA females were more sensitive only to the hypnotic effects of pentobarbital, probably because of a smaller apparent volume of distribution. No strain difference was observed in the hypnotic effect or clearance of barbital. These observations suggest that, in spite of a differential sensitivity to ethanol, the LA and MA lines do not differ in their response to the barbiturates tested.     

Central nervous system hemangioblastomas, endolymphatic sac tumors, and von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is a hereditary cancer syndrome caused by germline mutations of the VHL tumor suppressor gene. Major progress has been made in the last decade in both clinical and fundamental aspects of VHL. The VHL gene product, pVHL, has major and multiple functions: pVHL regulates not only first angiogenesis but also extracellular matrix formation and the cell cycle. A molecular diagnosis of VHL is now available, leading to a transformation in clinical management of patients and their families. Diagnosis of VHL has to be suspected in patients with a VHL-related tumor without familial history and especially in case of hemangioblastoma or endolymphatic sac tumors. Such patients should be systematically investigated for clinical and molecular evidence of VHL disease. Treatment of symptomatic hemangioblastomas remains mainly neurosurgical, often in emergency, but stereotactic radiosurgery is emerging as an alternative therapeutic procedure. In the future, antiangiogenic drugs could represent a potential medical treatment of CNS hemangioblastomas in view of their highly vascular structure. Lastly, visceral manifestations of VHL disease are also of critical importance and require early detection for effective treatment. Received: 22 January 2000 / Accepted: 21 February 2000     

亚甲基四氢叶酸还原酶基因多态性与甘肃汉族2型糖尿病肾病的关系

目的 研究亚甲基四氢叶酸还原酶(MTHFR)基因多态性与汉族2型糖尿病肾病的关系。方法 应用聚合酶链反应—限制性片段长度多态性的方法，检测甘肃汉族人2型糖尿病患者91例，其中单纯糖尿病组50例，糖尿病肾病组41例，正常对照组35例，比较各组间MTHFR等位基因和基因型频率。结果 纯合基因型TT和杂合基因型CT在糖尿病肾病组的频率为34．1％和51．2％，高于糖尿病组(16％和48％)和正常对照组(14.3％和25．7％)，糖尿病肾病组的等位基因T频率(59．8％)也高于糖尿病组(40％)和正常对照组(27．1％)，差异均有统计学意义，糖尿病组和正常对照组之间的分布无统计学差异。结论 MTHFR基因C677T变异与甘肃汉族2型糖尿病患者糖尿病肾病的发病有关，等位基因T可能是糖尿病肾病的易感基因。