Plasma aldosterone level in a female case of pseudohyperaldosteronism (Liddle's syndrome)

A 22-yr-old female suffering from hypertension, hypokalemic alkalosis and suppressed plasma renin activity was studied. The plasma aldosterone concentration (PAC) ranged between subnormal and normal levels while the other adrenal mineralocorticoids were normal. Examinations through computed tomography and ultrasonography showed no abnormal findings. For differential diagnosis, dexamethasone, spironolactone and triamterene were administered. Triamterene alone corrected the abnormalities in this case, and the therapeutic effect was further enhanced by sodium restriction. Therefore, the present case is strongly suggested to be one of Liddle's syndrome, which is characterized by a primary defect in renal tubular sodium handling and can be corrected with triamterene. However, the patient in our study is different from the first reported case in which aldosterone secretion was estimated to be low. Analysis of the changes in PAC has shown that PAC is parallel with the level of plasma progesterone in accordance with the rhythm of the menstrual cycle and, in the follicular phase, PAC is rather low. It is concluded that the patient was suffering from Liddle's syndrome, and it is assumed that PAC is not always subnormal and, as same as in normal females, PAC may change in accordance with the rhythm of the menstrual cycle in a female case of Liddle's syndrome.     

Mohr syndrome in two siblings

The present study reports on two siblings of different sex, affected with a condition corresponding to Mohr syndrome. Characteristic symptoms such as epicanthic folds, a broad and flattened nasal root, a lobulated and hamartomatous tongue, poly- and syndactyly on both hands and feet, doubling of the big toes with less frequent features such as marked psychosomatic retardation and overall hypotony have been observed. All the cited anomalies have been of importance in the differential diagnosis. Difficulties associated with classification of new syndromes and the importance for practical clinical genetics of distinguishing between them are discussed.     

Cystic fibrosis transmembrane conductance regulator inhibits epithelial Na+ channels carrying Liddle's syndrome mutations.

Epithelial Na+ channels (ENaC) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) upon activation by protein kinase A. It is, however, still unclear how CFTR regulates the activity of ENaC. In the present study we examined whether CFTR interacts with ENaC by interfering with the Nedd4- and ubiquitin-mediated endocytosis of ENaC. Various C-terminal mutations were introduced into the three alpha-, beta-, and gamma-subunits of the rat epithelial Na+ channel, thereby eliminating PY motifs, which are important binding domains for the ubiquitin ligase Nedd4. When expressed in Xenopus oocytes, most of the ENaC stop (alpha-H647X, beta-P565X, gamma-S608X) or point (alpha-P671A, beta-Y618A, gamma-P(624-626)A) mutations induced enhanced Na+ currents when compared with wild type alpha,beta,gamma-rENaC. However, ENaC currents formed by either of the mutant alpha-, beta-, or gamma-subunits were inhibited during activation of CFTR by forskolin (10 micromol/l) and 3-isobutyl-1-methylxanthine (1 mmol/l). Antibodies to dynamin or ubiquitin enhanced alpha,beta,gamma-rENaC whole cell Na+ conductance but did not interfere with inhibition of ENaC by CFTR. Another mutant, beta-T592M,T593A-ENaC, also showed enhanced Na+ currents, which were down-regulated by CFTR. Moreover, activation of ENaC by extracellular proteases and xCAP1 does not disturb CFTR-dependent inhibition of ENaC. We conclude that regulation of ENaC by CFTR is distal to other regulatory limbs and does not involve Nedd4-dependent ubiquitination.     

Effect of subunit composition and Liddle's syndrome mutations on biosynthesis of ENaC

The epithelialNa⁺ channel (ENaC) is comprised ofthree homologous subunits: , , and , all of which are requiredfor formation of the fully functional channel. This channel isresponsible for salt reabsorption in the kidney, the airway, and thelarge bowel. Mutations in ENaC can cause human disease by increasingchannel function in Liddle's syndrome, a form of hereditaryhypertension, or by decreasing channel function inpseudohypoaldosteronism type I, a salt-wasting disease of infancy. Wepreviously showed that ENaC is expressed on the cell surface as aminimally glycosylated, Triton-insoluble protein. In the presentstudy we found that ENaC existed initially as a Triton-soluble proteinthat contained high-mannose glycosylation, presumably in theendoplasmic reticulum. This form of the protein disappeared as theTriton-insoluble, minimally glycosylated form became the more prevalentspecies. In pulse-chase studies of individually expressed subunits, wefound that the Triton-soluble form of -ENaC accumulated initially,whereas the Triton-soluble form of -ENaC decreased throughout thetime course. However, when all three subunits were coexpressed, the- and -subunits showed a similar pattern. The complex becameTriton insoluble at some point after the endoplasmic reticulum, asincubation at 15°C blocked the conversion to the insoluble form.Deletion of the carboxy-terminal tail of -ENaC causes Liddle'ssyndrome. This mutation increased the amount of newly synthesizedTriton-insoluble ENaC heteromultimers but did not affect the half-lifeof insoluble protein. Therefore, subunit composition and mutations inindividual subunits can influence biosynthesis of the ENaC complex.

     

Two cases of nevoid basal cell carcinoma syndrome

Motivated by the diagnosis and treatment of two cases of nevoid or Goltz-Gorlin syndrome, we have taken a brief look at the literature and present these two cases, which display the four principal features defining this syndrome: multiple basal cell carcinomas, maxillary cysts, skeletal anomalies, and ectopic calcifications. Certain aspects are emphasized, including the association in one of them of basal cell carcinomas with a cystic adenoma or Brooke's tumor, which, although described by other authors, is infrequent.