0000000000681252
AUTHOR
Xavier Jeunemaitre
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron
Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron. Using combined linkage analysis and whole-exome sequencing in two families, we identified KLHL3 as a third gene responsible for FHHt. Direct sequencing of 43 other affected individuals revealed 11 additional missense mutations that were associated with heterogeneous phenotypes and diverse modes of inheritance. Polymorphisms at KLHL3 were not associated with blood pressure. The KLHL3 protein belongs to the BTB-BACK-kelch family of actin-binding proteins tha…
Compliance and Pulse Wave Velocity Assessed by MRI Detect Early Aortic Impairment in Young Patients With Mutation of the Smooth Muscle Myosin Heavy Chain
Purpose To evaluate aortic elasticity with MRI on young asymptomatic individuals with mutation of the smooth muscle myosin heavy chain in whom aortic enlargement is not present. Materials and Methods Aortic compliance, aortic distensibility, and pulse wave velocity (PWV) were semiautomatically measured from MRI in 8 asymptomatic subjects having a mutation of the MYH11 gene (M+) and 21 nonmutated relatives (M−) of similar age, sex, and blood pressure characteristics. Results Despite a similar aortic diameter in both groups, the aortic compliance and distensibility were significantly lower in M+ subjects compared with M− (0.84 ± 0.33 versus 2.03 ± 0.54 mm2/mmHg, 1.18 ± 0.62 10−3 versus 5.11 ±…
Should aortic stiffness be evaluated in thoracic aortic aneurysm/dissection relatives to prevent risks?
International audience
Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus
We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection ( TAAD) and patent ductus arteriosus (PDA)(1,2) and mapped the disease locus to 16p12.2-p13.13 (ref. 3). We now demonstrate that the disease is caused by mutations in the MYH11 gene affecting the C-terminal coiled-coil region of the smooth muscle myosin heavy chain, a specific contractile protein of smooth muscle cells (SMC). All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness. Examination of pathological aortas showed large areas of medial degeneration with very low SMC content. Abnormal immunological recognition of SM-MHC and the colocal…
Familial thoracic aortic aneurysm/dissection with patent ductus arteriosus: genetic arguments for a particular pathophysiological entity.
International audience; Thoracic aortic aneurysm and aortic dissection (TAA and AD) are an important cause of sudden death. Familial cases could account for 20% of all cases. A genetic heterogeneity with two identified genes (FBN1 and COL3A1) and three loci (3p24-25 or MFS2/TAAD2, 5q13-q14 and 11q23.2-24) has been shown previously. Study of a single family composed of 179 members with an abnormally high occurrence of TAA/AD disease. A total of 40 subjects from three generations were investigated. In addition to five cases of stroke and three cases of sudden death, there were four cases of AD and four cases of TAA in adults. In all, 11 cases of patent ductus arteriosus (PDA) were observed, t…