Genetics, clinical and pathological features of glomerulonephrites associated with mutations of nonmuscle myosin IIA (Fechtner syndrome)

被引:81
作者
Ghiggeri, GM
Caridi, G
Magrini, U
Sessa, A
Savoia, A
Seri, M
Pecci, A
Romagnoli, R
Gangarossa, S
Noris, P
Sartore, S
Necchi, V
Ravazzolo, R
Balduini, CL
机构
[1] IRCCS G Gaslini, Lab Pathophysiol Uremia, Genoa, Italy
[2] IRCCS San Matteo, Inst Pathol, Pavia, Italy
[3] IRCCS San Matteo, Dept Internal Med, Pavia, Italy
[4] Osped Vimercate, Nephrol Sect, Naples, Italy
[5] Telethon Inst Genet & Med, Naples, Italy
[6] Univ Bologna, I-40126 Bologna, Italy
[7] Univ Siena, Inst Physiol, I-53100 Siena, Italy
[8] CNR, Ctr Muscle Biol & Physiopathol, Dept Biomed Sci, Padua, Italy
[9] Univ Pavia, I-27100 Pavia, Italy
[10] IRCCS, Genet Mol Lab, Genoa, Italy
关键词
Alport-like syndrome; inherited glomerulonephrites; Fechtner syndrome (FTNS); nonmuscle myosin; podocin;
D O I
10.1053/ajkd.2003.50028
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background: Fechtner syndrome (FTNS), also known as Alport-like syndrome, is a rare inherited condition characterized by progressive nephritis, macrothrombocytopenia, Dohle-like leukocyte inclusions, deafness, and cataract. Although it recently was shown that FTNS derives from mutation of MYH9, the gene for the heavy chain of nonmuscle myosin IIA (NMMHC-IIA), its pathophysiological characteristics remain unknown. Methods: We studied a large FTNS family in which 10 components carried a missense mutation of MYH9 determining the D1424H substitution. Results: All affected subjects presented with macrothrombocytopenia and leukocyte Dohle-like bodies consisting of macroaggregates of NMMHC-IIA, but only two subjects had major renal problems characterized by proteinuria and renal failure. Electron microscopy showed focal and segmental effacement of podocytes and loss of the interpodocyte slit diaphragm. Immunohistochemistry showed apical localization of NMMHC-IIA in tubular epithelia and less podocyte staining in the two patients, whereas it was diffuse in normal epithelia. Three patients presented with stable microhematuria, and another five patients had no renal lesions, although they carried the same mutation of MYH9. Therefore, MYH9 mutation per se was responsible for platelet and leukocyte abnormalities, whereas additional predisposing conditions and/or environmental factors are necessary for nephropathy, cataract, and deafness. Looking at podocyte components conferring permselectivity properties to the kidney, we characterized the haplotype of podocin and found cosegregation of one specific allele in the two patients with nephrotic syndrome, suggesting a relationship between podocin features and proteinuria. Conclusion: Our study indicates a major role for the NMMHC-IIA abnormality in the pathogenesis of leukocyte, platelet, and kidney defects in FTNS. The basic feature in all cases is aggregation and compartmentation of NMMHC-IIA. However, proteinuria and podocyte lesions are the hallmark of nephropathy in patients who develop renal failure, and podocin may have some function in this setting.
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页码:95 / 104
页数:10
相关论文
共 33 条
[1]  
ALPORT AC, 1927, BRIT MED J, V1, P540
[2]  
Arrondel C, 2002, J AM SOC NEPHROL, V13, P65, DOI 10.1681/ASN.V13165
[3]   A millennial myosin census [J].
Berg, JS ;
Powell, BC ;
Cheney, RE .
MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (04) :780-794
[4]   NONMUSCLE AND SMOOTH-MUSCLE MYOSIN ISOFORMS IN BOVINE ENDOTHELIAL-CELLS [J].
BORRIONE, AC ;
ZANELLATO, AMC ;
GIURIATO, L ;
SCANNAPIECO, G ;
PAULETTO, P ;
SARTORE, S .
EXPERIMENTAL CELL RESEARCH, 1990, 190 (01) :1-10
[5]   NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome [J].
Boute, N ;
Gribouval, O ;
Roselli, S ;
Benessy, F ;
Lee, H ;
Fuchshuber, A ;
Dahan, K ;
Gubler, MC ;
Niaudet, P ;
Antignac, C .
NATURE GENETICS, 2000, 24 (04) :349-354
[6]  
Caridi G, 2001, J AM SOC NEPHROL, V12, P2742, DOI 10.1681/ASN.V12122742
[7]   INCLUSIONS OF MAY-HEGGLIN ANOMALY AND DOHLE BODIES OF INFECTION - ULTRASTRUCTURAL COMPARISON [J].
CAWLEY, JC ;
HAYHOE, FGJ .
BRITISH JOURNAL OF HAEMATOLOGY, 1972, 22 (04) :491-&
[8]  
CHIAVEGATO A, 1995, VIRCHOWS ARCH, V426, P77
[9]   Localisation of the gene responsible for Fechtner syndrome in a region <600 Kb on 22q11-q13 [J].
Cusano, R ;
Gangarossa, S ;
Forabosco, P ;
Caridi, G ;
Ghiggeri, GM ;
Russo, G ;
Iolascon, A ;
Ravazzolo, R ;
Seri, M .
EUROPEAN JOURNAL OF HUMAN GENETICS, 2000, 8 (11) :895-899
[10]  
DRENCKHAHN D, 1988, LAB INVEST, V59, P673