Simultaneous Homozygous Mutations in SLC12A3 and CLCNKB in an Inbred Chinese Pedigree

Abstract

Gitelman syndrome (GS) and Bartter syndrome (BS) type III are both rare, recessively inherited salt-losing tubulopathies caused by SLC12A3 and CLCNKB mutations, respectively. We described a 48-year-old male patient with fatigue, carpopedal spasm, arthralgia, hypokalemic alkalosis, mild renal dysfunction, hypomagnesemia, hypocalciuria, hyperuricemia, normotension, hyperreninemia and chondrocalcinosis in knees and Achilles tendons. His parents are first cousin. Genetic analysis revealed simultaneous homozygous mutations in SLC12A3 gene with c.248G>A, p.Arg83Gln and CLCNKB gene with c.1171T>C, p.Trp391Arg. The second younger brother of the proband harbored the same simultaneous mutations in SLC12A3 and CLCNKB and exhibited similar clinical features except normomagnesemia and bilateral kidney stones. The first younger brother of the proband harbored the same homozygous mutations in CLCNKB and exhibited clinical features of hypokalemia, normomagnesemia, hypercalciuria and hyperuricemia. Potassium chloride, spironolactone and potassium magnesium aspartate were prescribed to the proband to correct electrolytic disturbances. Benzbromarone and febuxostat were prescribed to correct hyperuricemia. The dose of potassium magnesium aspartate was subsequently increased to alleviate arthralgia resulting from calcium pyrophosphate deposition disease (CPPD). To the best of our knowledge, we are the first to report an exceptionally rare case in an inbred Chinese pedigree with simultaneous homozygous mutations in SLC12A3 and CLCNKB. GS and BS type III have significant intrafamilial phenotype heterogeneity. When arthralgia is developed in patients with GS and BS, gout and CPPD should both be considered.

Keywords: Bartter syndrome; CLCNKB; Gitelman syndrome; SLC12A3; calcium pyrophosphate deposition disease; gout.

Figure 1

Sequence analyses of the SLC12A3 gene and the identified SLC12A3 mutations. (A) A homozygous mutation (red arrow) (c.248G>A, p.Arg83Gln)in SLC12A3 was identified in the proband and II-2,II-4, (B) A heterozygous mutation (red arrow) (c.248G>A, p.Arg83Gln) in SLC12A3 was identified in I-1,I-2,III-1.

Figure 2

Sequence analyses of the CLCNKB gene and the identified CLCNKB mutations. (A) A homozygous mutation red arrow) (c.1171T>C, p.Trp391Arg) in CLCNKB was identified in the index patient and II-3, II-4. (B) A heterozygous mutation (red arrow) (c.1171T>C, p.Trp391Arg) in CLCNKB was identified in t I-1, I-2, II-5, III-1.

Figure 3

Phylogenetic conservation analysis. The amino acid residues altered by the corresponding variants studied here were highlighted. The phylogenetic conservation analysis revealed that the residues of 83 in NCC (A) and 391 in ClC-Kb (B) were both highly conserved across species.

Figure 4

Pedigree of the family shows that the clinical phenotype cosegregates with simultaneous homozygous mutations in SLC12A3 and CLCNKB. The arrow indicates the index patient (II-2). Males and females are indicated by squares and circles, respectively.

Figure 5

X-ray of joints. (A) Anteroposterior projections of the patient’s knees. Extensive chondrocalcinosis of the fibrocartilage of the medial and lateral menisci (arrows) is present. (B) Lateral projections of the ankles. Calcification of the Achilles tendons is present.