Mutations in ROMK1 potassium channel gene (KCNJ1) causes antenatal/neonatal Bartter\'s syndrome type II, which presents with renal salt wasting, hypokalemic metabolic alkalosis, secondary hyperaldosteronism, hypercalciuria, and nephrocalcinosis. We herein describe a case of late-onset Bartter\'s syndrome type II with progressive renal failure requiring renal replacement therapy secondary to a novel homozygous missense mutation in Exon 2 of KCNJ1 gene (c.500G>A). With this case, we aim to highlight the need for a high index of suspicion and the role of genetic evaluation to diagnose clinically unclassified cases of nephrocalcinosis with renal electrolyte abnormalities more so in late and atypical presentations.

BACKGROUND: In recent years, morbidity and mortality from colorectal cancer have increased. Colorectal adenoma is the main precancerous lesion. Understanding the pathogenesis of colorectal adenoma will help to improve the early diagnosis rate of colorectal cancer.
METHODS: In this case-control study, we focused on three single nucleotide polymorphisms (SNPs) in genes SLC8A1 (rs4952490), KCNJ1 (rs2855798), and SLC12A1 (rs1531916). We analyzed 207 colorectal adenoma patients (112 high-risk cases and 95 low-risk cases) and 212 control subjects by Sanger sequencing. A food frequency questionnaire (FFQ) was used to survey demographic characteristics and dietary nutrition.
RESULTS: In the overall analysis, the results suggested that the AA+AG and AG genotype carriers of rs4952490 had a 73.1% and 78% lower risk of colorectal adenoma compared to GG genotype carriers, respectively. However rs2855798 and rs1531916 were not associated with the incidence of colorectal adenoma. Additionally, stratified analysis showed that rs4952490 AA+AG and AG genotypes had a protective effect against low-risk colorectal adenoma in patients aged ≤ 60 years old who were non-smokers. We also observed that when calcium intake was higher than 616 mg/d and patients carried at least one gene with variant alleles there was a protective effect against low-risk colorectal adenoma.
CONCLUSIONS: Interactions between dietary calcium intake and calcium reabsorption genes may affect the occurrence and development of colorectal adenoma.

Basolateral potassium channels in the distal convoluted tubule (DCT) are composed of inwardly-rectifying potassium channel 4.1 (Kir4.1) and Kir5.1. Kir4.1 interacts with Kir5.1 to form a 40 pS K+ channel which is the only type K+ channel expressed in the basolateral membrane of the DCT. Moreover, Kir4.1/Kir5.1 heterotetramer plays a key role in determining the expression and activity of thiazide-sensitive Na-Cl cotransport (NCC). In addition to Kir4.1/Kir5.1, Kir1.1 (ROMK) is expressed in the apical membrane of the late DCT (DCT2) and plays a key role in mediating epithelial Na+ channel (ENaC)-dependent K+ excretion. High dietary-K+-intake (HK) stimulates ROMK and inhibits Kir4.1/Kir5.1 in the DCT. Inhibition of Kir4.1/Kir5.1 is essential for HK-induced suppression of NCC whereas the stimulation of ROMK is important for increasing ENaC-dependent K+ excretion during HK. We have now used the patch-clamp-technique to examine whether gender and Cl- content of K+-diet affect HK-induced inhibition of basolateral Kir4.1/Kir5.1 and HK-induced stimulation of ROMK. Single-channel-recording shows that basolateral 40 pS K+ channel (Kir4.1/Kir5.1) activity of the DCT defined by NPo was 1.34 (1% KCl, normal K, NK), 0.95 (5% KCl) and 1.03 (5% K+-citrate) in male mice while it was 1.47, 1.02 and 1.05 in female mice. The whole-cell recording shows that Kir4.1/Kir5.1-mediated-K+ current of the early-DCT (DCT1) was 1,170 pA (NK), 725 pA (5% KCl) and 700 pA (5% K+-citrate) in male mice whereas it was 1,125 pA, 674 pA and 700 pA in female mice. Moreover, K+-currents (IK) reversal potential of DCT (an index of membrane potential) was -63 mV (NK), -49 mV (5% KCl) and -49 mV (5% K-citrate) in the male mice whereas it was -63 mV, -50 mV and -50 mV in female mice. Finally, TPNQ-sensitive whole-cell ROMK-currents in the DCT2 /initial-connecting tubule (CNT) were 910 pA (NK), 1,520 pA (5% KCl) and 1,540 pA (5% K+-citrate) in male mice whereas the ROMK-mediated K+ currents were 1,005 pA, 1,590 pA and 1,570 pA in female mice. We conclude that the effect of HK intake on Kir4.1/Kir5.1 of the DCT and ROMK of DCT2/CNT is similar between male and female mice. Also, Cl- content in HK diets has no effect on HK-induced inhibition of Kir4.1/Kir5.1 of the DCT and HK-induced stimulation of ROMK in DCT2/CNT.

Nephrolithiasis is not common in children, but the incidence is gradually increased in these years. Urinary tract malformations, urinary infection, dietary habits, geographic region and genetic factor are involved in the etiology of nephrolithiasis. For the affected child, it is especially important to elucidate the etiology, which may provide an accurate diagnosis, a personalized therapy and effective follow-up strategy. Here to seek the etiology of a ten-year-old boy incidentally found with nephrolithiasis, next generation sequencing (NGS) including a panel with 248 genes involved in hereditary kidney diseases was performed for the boy and identified two mutations of KCNJ1, c.89G > A (p.C30Y) and c.65G > T (p.R22M), and the later was a novel missense mutation originated from his father. The child was confirmed with type II Bartter syndrome (BS) caused by KCNJ1 mutations. Our study suggests that BS may be difficult to get diagnosed at an early stage based on clinical manifestations or biochemical laboratory tests, and NGS is an efficient way to determine the etiology and provide further treatment and guide fertility counseling for the affected family.

Monogenic causes of paediatric nephrocalcinosis are associated with extensive phenotypic variability. We report a 14-year-old male who presented at 8 years of age with incidentally identified nephrocalcinosis alongside growth impairment and dental anomalies. Extensive genetic investigation confirmed a molecular diagnosis of Bartter syndrome type II. This is exceptional in both late presentation and the presence of amelogenesis imperfecta, a very rare association of inherited tubulopathies. Details of the nephrocalcinosis gene panel analysed and associated phenotypes are presented to highlight the utility of a phenotype-driven genetic panel in resolving an atypical presentation of nephrocalcinosis, allowing precise diagnosis, tailored therapy and prognostication.

暂无摘要。

Bartter\'s disease, an inherited renal tubular disorder is due to a defect in ion transport across the ascending limb of the loop of Henle leading to failure of the ability of kidneys to concentrate urine and hence polyuria. We present three fetuses of mothers with severe polyhydramnios with normal maternal blood sugar profile, routine Toxoplasma, Rubella, Cytomegalovirus, Herpes (TORCH) serology. The ultrasound showed no structural anomaly in the fetus, but consistent overdistended bladder with severe polyhydramnios was observed without any evidence of obstructive uropathy. The biochemical test on amniotic fluid was suggestive of Bartter\'s disease in case 1 and borderline in case 2, and next-generation sequencing confirmed a mutation of KCNJ1 associated with Bartter\'s disease Type II in case 1 and a mutation in SLC21A1 in case 2. Amniotic fluid biochemistry was inconclusive in case 3. A consistent full bladder with severe polyhydramnios with onset around 24 to 25 weeks was a novel finding which was observed due to fetal polyuria and can be used as a clue to investigate cases with severe polyhydramnios with no structural anomaly. Antenatal diagnosis will help in the proper management of child and genetic counseling for the next pregnancy.

Bartter syndrome (BS) is a hereditary condition transmitted as an autosomal recessive (Bartter type 1 to 4) or dominant trait (Bartter type 5). The disease associates hypokalemic alkalosis with varying degrees of hypercalciuria. Here we presented a case (BS type Ⅱ) of a 17 years old female presented with polyhydramnios, polyuria, nephrocalcinosis and hypokalemia, which was alleviated after treatment with celecoxib and vitamin D(3). DNA sequencing identified compound heterozygous KCNJ1 gene mutations, c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), with the latter a novel mutation. Her father and mother were heterozygous carriers of c. 931C >T (p.R311W) and c. 445-446insCCTGAACAC (p.V149Afs, 150X), respectively. In conclusion, this case of BS type Ⅱ is caused by a novel compound heterozygous KCNJ1 mutation. Further studies are needed to verify the effect of celecoxib in BS patients.
通过对1例17岁女性Bartter综合征(BS)Ⅱ型患者临床和基因研究，探讨BSⅡ型的遗传机制及治疗。收集临床资料，提取患者及其父母的外周血白细胞DNA，扩增并测序确定KCNJ1基因突变。本例患者母亲妊娠期羊水过多，其婴儿期开始多饮多尿，检查发现肾结石及低钾血症，给予塞来昔布及维生素D(3)治疗，症状改善。KCNJ1基因分析显示c.931C>T(p.R311W)和c.445-446insCCTGAACAC(p.V149Afs，150X)复合杂合突变，后者为首次报告。父母分别为携带杂合子。KCNJ1新的复合杂合突变是本例BSⅡ型的遗传基础。塞来昔布治疗值得在更多BS中加以验证。.

Mutations in the ROMK1 potassium channel gene (KCNJ1) cause antenatal/neonatal Bartter syndrome type II (aBS II), a renal disorder that begins in utero, accounting for the polyhydramnios and premature delivery that is typical in affected infants, who develop massive renal salt wasting, hypokalaemic metabolic alkalosis, secondary hyperreninaemic hyperaldosteronism, hypercalciuria and nephrocalcinosis. This BS type is believed to represent a disorder of the infancy, but not in adulthood. We herein describe a female patient with a remarkably late-onset and mild clinical manifestation of BS II with compound heterozygous KCNJ1 missense mutations, consisting of a novel c.197T > A (p.I66N) and a previously reported c.875G > A (p.R292Q) KCNJ1 mutation. We implemented and evaluated the performance of two different bioinformatics-based approaches of targeted massively parallel sequencing [next generation sequencing (NGS)] in defining the molecular diagnosis. Our results demonstrate that aBS II may be suspected in patients with a late-onset phenotype. Our experimental approach of NGS-based mutation screening combined with Sanger sequencing proved to be a reliable molecular approach for defining the clinical diagnosis in our patient, and results in important differential diagnostic and therapeutic implications for patients with BS. Our results could have a significant impact on the diagnosis and methodological approaches of genetic testing in other patients with clinical unclassified phenotypes of nephrocalcinosis and congenital renal electrolyte abnormalities.

The SLC8A1 (solute carrier family 8, member 1) gene, encoding Na+ /Ca2+ exchanger, is essential in regulating calcium reabsorption and homeostasis. Calcium homeostasis plays a key role in cell proliferation and apoptosis. We hypothesized that polymorphisms in five calcium-regulating genes (SLC8A1, ATP2B1, CALB1, CALB2, and CABP1) interact with calcium intake in relation to the risk of colorectal neoplasia. A two-phase (discovery and replication) study was conducted within the Tennessee Colorectal Polyp Study, including a total of 1275 cases and 2811 controls. In Phase I, we identified six out of 135 SNPs that significantly interacted with calcium intake in relation to adenoma risk. In Phase II, the calcium intake by rs4952490 (SLC8A1) interaction was replicated (Pinteraction  = 0.048). We found an inverse association between calcium intake (1000-2000 mg/day) and colorectal adenomas, particularly for multiple/advanced adenomas, among the G-allele carriers but not among homozygous carriers of the common variant (A) in rs4952490. In the joint analysis of SLC8A1, KCNJ1, and SLC12A1 SNPs, carriers of variant alleles in at least two genes and with calcium intake above the DRI (1000 mg/day) were approximately 30-57% less likely to have adenomas than those whose calcium intake was below the DRI. The association was stronger for multiple/advanced adenomas. No association was found among those who did not carry any variant alleles in these genes when calcium intake was below 2500 mg/day. These findings, if confirmed, may provide a new avenue for the personalized prevention of colorectal adenoma and cancer.