Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease.
Recent linkage analyses of nondiabetic African-American patients with focal segmental glomerulosclerosis (FSGS) have identified MYH9, encoding nonmuscle myosin heavy chain IIA (NMMHC-IIA), as a gene having a critical role in this disease. Abnormalities of the MYH9 locus also underlie rare autosomal dominant diseases such as May-Hegglin anomaly, and Sebastian, Epstein (EPS), and Fechtner (FTNS) syndromes that are characterized by macrothrombocytopenia and cytoplasmic inclusion bodies in granulocytes. Among these diseases, patients with EPS or FTNS develop progressive nephritis and hearing disability. We analyzed clinical features and pathophysiological findings of nine EPS-FTNS patients with MYH9 mutations at the R702 codon hot spot. Most developed proteinuria and/or hematuria in early infancy and had a rapid progression of renal impairment during adolescence. Renal histopathological findings in one patient showed changes compatible with FSGS. The intensity of immunostaining for NMMHC-IIA in podocytes was decreased in this patient compared with control patients. Thus, MYH9 R702 mutations display a strict genotype-phenotype correlation, and lead to the rapid deterioration of podocyte structure. Our results highlight the critical role of NMMHC-IIA in the development of FSGS.
Sekine
Takashi
T
Faculty of Medicine, Department of Pediatrics, The University of Tokyo, Tokyo, Japan. sekinet-tky@umin.ac.jp
Konno
Mutsuko
M
Sasaki
Satoshi
S
Moritani
Suzuko
S
Miura
Takuma
T
Wong
Wai-shan
WS
Nishio
Hisanori
H
Nishiguchi
Toshihiro
T
Ohuchi
Miyako Yoshinari
MY
Tsuchiya
Shigeru
S
Matsuyama
Takeshi
T
Kanegane
Hirokazu
H
Ida
Komei
K
Miura
Kenichiro
K
Harita
Yutaka
Y
Hattori
Motoshi
M
Horita
Shigeru
S
Igarashi
Takashi
T
Saito
Hidehiko
H
Kunishima
Shinji
S
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D008297:Male; D020409:Molecular Motor Proteins / Q000235:genetics*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D009394:Nephritis, Hereditary / Q000235:genetics; D011507:Proteinuria / Q000209:etiology*; D013921:Thrombocytopenia / Q000235:genetics / Q000151:congenital; D055815:Young Adult
C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains