MYO1E Mutations Drive Autosomal Recessive Familial Focal Segmental Glomerulosclerosis

An international team of researchers has linked 2 mutations in the MYO1E gene to an inherited form of focal segmental glomerulosclerosis, a disorder affecting the kidneys [N Engl J Med. 2011;365(4):295-306]. The A159P and Y695X mutations were identified in patients whose disease had been diagnosed in childhood and demonstrated resistance to glucocorticoid treatment. MYO1E encodes myosin 1E (Myo1E), a protein that promotes homeostasis of the podocytes and helps preserve the integrity of the glomerular filtration barrier.

The study, which focused largely on 2 families with multiple children afflicted with focal segmental glomerulosclerosis, discovered that only individuals with 2 copies of either mutation developed the disorder; several family members with only 1 copy of either gene were unaffected. Of the hundreds of healthy controls screened, none had either mutation. These findings lend further support to the notion that the familial form of focal segmental glomerulosclerosis is autosomal recessive, and the authors hypothesized that “Myo1E-associated focal segmental glomerulosclerosis might be restricted to families with some degree of consanguinity.”

The study started with a family from Italy that had 3 children with focal segmental glomerulosclerosis (the Index family). Whole-genome linkage analysis was performed for multiple family members spanning 4 generations. Results were compared with results of DNA analyses for 52 individuals with familial recessive (n=28) or sporadic childhood-onset (n=24) focal segmental glomerulosclerosis and with 484 healthy controls from Italy (n=382) and Turkey (n=102). The only patient outside the index family positive for a homozygous MYO1E mutation was a 14-year-old Turkish girl; it was learned that her older sister had died from end-stage renal disease at age 6, and her family (Family 2) was selected for additional study. Although no DNA was available for the deceased daughter, her kidney disorder had been confirmed during her lifetime by renal biopsy, and these results were available to the investigators.

The 3 affected children in the Index family were positive for a homozygous A159P mutation, which was found to cause impaired podocyte motility and impaired Myo1E expression. These children’s parents and their unaffected brother had a single A159P allele. The surviving daughter in Family 2 had two Y695X alleles. Immunohistochemical staining of her glomeruli revealed odd ultrastructural features, including a thickened and disorganized glomerular basement membrane, and the authors said these findings are consistent with studies involving Myo1E-deficient mice.

All surviving affected children in the families had received cyclosporine and an angiotensin-converting enzyme inhibitor, in addition to glucocorticoids. One child was resistant to all therapies, while the remaining 3 children had partial responses to the other 2 agents, with a decrease in proteinuria. The investigators said cyclosporine “reduces proteinuria in up to 70% of patients with glucocorticoid-resistant focal segmental glomerulosclerosis,” and studies suggest this benefit is likely due to the drug’s ability to stabilize the podocyte cytoskeleton and not to its immunosuppressive properties.

Despite the initial effectiveness of cyclosporine therapy at reducing proteinuria, between 40% and 60% of patients with glucocorticoid-resistant focal segmental glomerulosclerosis relapse. Including the deceased daughter, 1 child in each family developed end-stage renal disease. The authors said it was possible that earlier diagnosis and more effective antiproteinuric treatment had lessened disease severity in the other children. Despite confirming a new genetic driver of this nephrotic disorder, the authors said, “MYO1E mutations do not appear to be a common cause of focal segmental glomerulosclerosis, since we have found only 2 independent MYO1E mutations among 29 unrelated patients with familial focal segmental glomerulosclerosis and none among those with sporadic cases.”

Other genetic mutations found to play a role in a small percentage of cases of focal segmental glomerulosclerosis are NPHS1, NPHS2, and WT1 mutations. No patient in this study tested positive for any of these genes, indicating the need for research into other possible genetic contributors.