COQ6 Mutations in Children With Steroid-Resistant Focal Segmental Glomerulosclerosis and Sensorineural Hearing Loss.

The phenotypic combination of steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) and sensorineural hearing loss has been mainly reported in patients with mitochondrial cytopathies, including primary coenzyme Q10 (CoQ10) deficiency. In this report of 10 children with SR-FSGS and sensorineural hearing loss, we found 6 patients with biallelic COQ6 mutations. Median age at the onset of nephrotic syndrome was 29 (range, 15-47) months. All patients progressed to end-stage renal disease within a median of 13 (range, 1-27) months after the onset. Kidney biopsy revealed abnormal mitochondrial proliferation in podocytes in all 6 patients. None of the 5 patients who underwent kidney transplantation developed recurrence of FSGS. Primary CoQ10 deficiency due to COQ6 mutations should be considered in children presenting with both SR-FSGS and sensorineural hearing loss. An early diagnosis of COQ6 mutations is essential because the condition is treatable when CoQ10 supplementation is started at the early stage. We recommend early kidney biopsy because detection of abnormal mitochondrial proliferation in podocytes might provide an earlier diagnostic clue.

The first Korean case of lysinuric protein intolerance: presented with short stature and increased somnolence.

Lysinuric protein intolerance (LPI) is a rare inherited metabolic disease, caused by defective transport of dibasic amino acids. Failure to thrive, hepatosplenomegaly, hematological abnormalities, and hyperammonemic crisis are major clinical features. However, there has been no reported Korean patient with LPI as of yet. We recently encountered a 3.7-yr-old Korean girl with LPI and the diagnosis was confirmed by amino acid analyses and the SLC7A7 gene analysis. Her initial chief complaint was short stature below the 3rd percentile and increased somnolence for several months. Hepatosplenomegaly was noted, as were anemia, leukopenia, elevated levels of ferritin and lactate dehydrogenase, and hyperammonemia. Lysine, arginine, and ornithine levels were low in plasma and high in urine. The patient was a homozygote with a splicing site mutation of IVS4+1G > A in the SLC7A7. With the implementation of a low protein diet, sodium benzoate, citrulline and L-carnitine supplementation, anemia, hyperferritinemia, and hyperammonemia were improved, and normal growth velocity was observed.

Thioredoxin modulates activator protein 1 (AP-1) activity and p27Kip1 degradation through direct interaction with Jab1.

Thioredoxin (Trx) is a cellular redox enzyme that plays multiple roles in regulating cell growth and apoptosis. Jun activation domain-binding protein 1 (Jab1) was originally identified as a coactivator of activator protein 1 (AP-1) transcription and was also shown to promote degradation of the cyclin-dependent kinase inhibitor, p27Kip1. Recently, Jab1 expression was associated with the progression and poor prognosis of pituitary, epithelial ovarian, and breast cancers, suggesting that it plays a role in oncogenesis. Here, we report that Trx specifically interacts with and modulates the function of Jab1. Fluorescence resonance energy transfer and co-immunoprecipitation studies revealed that Trx and Jab1 colocalize and directly interact with each other. Further, Trx negatively regulates two important Jab1-controlled signaling pathways, activation of AP-1 transcription and degradation of p27Kip1, probably through a direct interaction between Trx and C-terminal of Jab1. The negative effect of Trx on AP-1 activity is Jab1-dependent, as it disappears when Jab1 levels are suppressed by an antisense approach. In addition, Trx competes with p27Kip1 for Jab1 binding. Taken together, our results suggest that Trx may regulate cell cycle and growth through a novel modulation of Jab1-mediated proliferation signals, further indicating that Trx may have the ability to control tumor progression.