Abstract. Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (∆L130 in exon 4 and W610X in exon 16) in the remaining four patients. ∆L130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, ∆L130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.

Key words complement component C3, compound heterozygous mutations, hereditary C3 deficiency, splice-site mutation.The complement system is a part of the innate immune system and plays an important role in host defense mechanisms. The pivotal complement factor C3 is the convergence point for the classical, lectin and alternative pathways of complement activation. C3 is synthesized predominantly by hepatocytes, although small amounts are also produced by activated monocytes, fibroblasts, endothelial cells, and smooth muscle cells. A single chain precursor (Pro-C3) of approximately 200 kDa is found intracellularly. This is then processed by proteolytic cleavage to yield the mature protein, which consists of two disulfide-linked subunits, a and b, with a molecular weight of 115 and 70 kDa, respectively. C3 is encoded by a 42-kb gene of 41 separate exons on chromosome 19. 1,2 Most of the patients with hereditary C3 deficiency are susceptible to recurrent bacterial infection. Some patients may develop immune-complex disorders such as glomerulonephritis and systemic lupus erythematosus. C3 deficiency has been described in 24 families including five Japanese. The detailed molecular basis of C3 deficiency has been investigated in only 12 families (14 individuals) including our reports, 3,4 representing a variety of ethnic and national origins. Almost all of the mutations were homozygous 5 except for a case of compound heterozygous we reported previously 4 and three cases (from two families) of suspected compound heterozygous after incomplete analysis. 6,7 Here we report the second confirmed case of hereditary C3 deficiency caused by novel compound heterozygous mutations. We detected mutations which consist of a nonsense and splice-site mutations, and further studied abnormal C3 transcripts derived from the splice mutation. Case reportThe patient was a 4-year-old Japanese boy who had suffered from two episodes of bacteremia caused by Streptococcus pneumoniae, pneumonia, acute otitis media, and gastroenterocolitis. His nonconsanguineous parents and his brother were all in good health. Laboratory examination of the patient revealed an extremely low level of serum C3 (0.3 mg/dL; normal range, 75-150 mg/dL) and CH 50 (4.7 U/mL; normal range, 35-45 U/ mL). Serum C3 levels of his mother, father, and brother were 40.0 mg/dL, 49.7 mg/dL, and 90.8 mg/dL, respectively. Serum C4 levels were all within normal range. Serum CH 50 levels of his mother, father, and brother were 31.7 U/mL, 42.8 U/mL, and 54.4 U/mL, respectively. Methods

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