MYO1E Mutations Linked to Glomerulosclerosis
MYO1E mutations are linked to glucocorticoid-resistant focal segmental glomerulosclerosis
THURSDAY, July 14 (HealthDay News) -- Mutations in the non-muscle class I myosin, myosin 1E (Myo1E) gene, MYO1E, are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis, according to a study published online July 13 in the New England Journal of Medicine.
Caterina Mele, Biol.Sci.D., from the Clinical Research Center for Rare Diseases in Bergamo, Italy, and colleagues performed whole-genome linkage analysis and high-throughput sequencing of the positive-linkage area in a family with autosomal recessive focal segmental glomerulosclerosis. A newly discovered gene was then sequenced in 52 unrelated patients with focal segmental glomerulosclerosis. Human kidney-biopsy specimens and cultured podocytes were examined immunohistochemically. The functional consequences of the mutations identified were characterized by in vitro expression studies.
The investigators identified two mutations (A159P and Y695X) in MYO1E, which segregated with focal segmental glomerulosclerosis in two independent pedigrees (the index family and family 2). Patients did not respond to glucocorticoid therapy, and were homozygous for the mutations. Thickening and disorganization of the glomerular basement membrane was identified on electron microscopy. Normal expression of Myo1E was reported in in vivo control human kidney-biopsy specimens and in in vitro glomerular. Abnormal subcellular localization and function of the A159P-Myo1E mutant was revealed on transfection studies. Loss of calmodulin binding and the tail domains of Myo1E was caused by Y695X mutation.
"MYO1E mutations are associated with childhood-onset, glucocorticoid-resistant focal segmental glomerulosclerosis. Our data provide evidence of a role of Myo1E in podocyte function and consequent integrity of the glomerular filtration barrier," the authors write.
Several study authors disclosed financial ties to the pharmaceutical industry; the editorial author disclosed financial relationships with medical publishing companies.