Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.

BACKGROUND: Five children from two consanguineous families presented with epilepsy beginning in infancy and severe ataxia, moderate sensorineural deafness, and a renal salt-losing tubulopathy with normotensive hypokalemic metabolic alkalosis. We investigated the genetic basis of this autosomal recessive disease, which we call the EAST syndrome (the presence of epilepsy, ataxia, sensorineural deafness, and tubulopathy). METHODS: Whole-genome linkage analysis was performed in the four affected children in one of the families. Newly identified mutations in a potassium-channel gene were evaluated with the use of a heterologous expression system. Protein expression and function were further investigated in genetically modified mice. RESULTS: Linkage analysis identified a single significant locus on chromosome 1q23.2 with a lod score of 4.98. This region contained the KCNJ10 gene, which encodes a potassium channel expressed in the brain, inner ear, and kidney. Sequencing of this candidate gene revealed homozygous missense mutations in affected persons in both families. These mutations, when expressed heterologously in xenopus oocytes, caused significant and specific decreases in potassium currents. Mice with Kcnj10 deletions became dehydrated, with definitive evidence of renal salt wasting. CONCLUSIONS: Mutations in KCNJ10 cause a specific disorder, consisting of epilepsy, ataxia, sensorineural deafness, and tubulopathy. Our findings indicate that KCNJ10 plays a major role in renal salt handling and, hence, possibly also in blood-pressure maintenance and its regulation.

Decreased spinal and femoral neck volumetric bone mineral density (BMD) in men with primary osteoporosis and their first-degree male relatives: familial effect on BMD in men.

OBJECTIVE: Low bone mass may be caused by a reduction in the amount of bone or density of bone or both. The purpose of this study was to examine differences in bone volume and volumetric bone mineral density (vBMD) in men with primary osteoporosis and their first-degree male relatives (FDMR). DESIGN: We used dual-energy X-ray absorptiometry (DXA) to measure areal density, then calculated bone volume and volumetric density in 121 men with primary osteoporosis, 73 FDMR and 66 normal men. We used regression methods adjusting for age, height and weight to determine deficits in bone volume and vBMD at the spine and femoral neck between men with spinal fractures due to primary osteoporosis, FDMR and normal men. RESULTS: Men with osteoporosis had a tendency to smaller bone volume in the spine and femoral neck (P = 0.08 and P = 0.09, respectively) and lower volumetric bone density at the spine (by about 50%) and femoral neck (by about 30%) compared with healthy controls (P < 0.0001). FDMR had no deficit in bone volume but did have lower volumetric density at the spine (by 10.2%) compared with healthy controls (P < 0.0001). CONCLUSIONS: A deficit in bone mineral accrual may underlie the pathogenesis of primary osteoporosis in men, resulting in low vBMD. This is likely to be determined by genetic factors, although shared common environmental factors may also be important.