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are unaff ected. Various names have been see original article on page 207 used, including giant syndrome (which leads to confusion with other Glomerular pathology in genetic causes of giant , including Bernard – Soulier syndrome), and non- autosomal dominant MYH9 muscle myosin IIA disorders (MYHIIA syndrome) and MYH9 disorders. spectrum disorders: what Recently, MYH9 risk variants have been associated with HIV-associ- are the clues telling us about ated collapsing glomerulopathy, FSGS, and hypertension-attributed end-stage among African-descent disease mechanism? populations.4 Th e term ‘MYH9 disor- J e f f r e y B . K o p p 1 ders ’ lumps together the autosomal dom- inant disorders and the kidney risk Genetic variation in MYH9, encoding non-muscle heavy chain IIA, variant. Th erefore a more distinctive has been recognized for over a decade as the cause of an autosomal and precise term is preferred for the former category, perhaps autosomal dominant syndrome characterized by macrothrombocytopenia, dominant MYH9 (ADM9) spectrum inclusions, and glomerular pathology. More recently, genetic disorders. The ADM9 spectrum com- variation in the MYH9 region on chromosome 22 has been associated prises at least five syndromes: May – with in African-descent individuals. A better Hegglin anomaly (OMIM 155100), understanding of the disease mechanisms responsible for glomerular Sebastian syndrome (OMIM 606249), injury in autosomal dominant MYH9 syndromes will lead to fuller Epstein syndrome (OMIM 153650), Fechtner syndrome (OMIM 153640), appreciation of the role of this gene in glomerular biology. and isolated sensorineural deafness Kidney International (2010) 78, 130 – 133. doi: 10.1038/ki.2010.82 (OMIM 603622). Glomerular pathology has been noted in Epstein and Fechtner syndromes, beginning with the original In this issue of Kidney International , basement membrane (GBM) pathology. reports describing these syndromes. Sekine and colleagues1 describe the renal Fourth, it demonstrates that the patho- Kidney abnormalities, the subject of a manifestations in nine patients with the logic picture can include segmental recent comprehensive review, 5 are seen in R702 in MYH9 , encoding glomerulosclerosis, at an early stage of about 30% – 70 % of ADM9 patients. nonmuscle myosin IIA heavy chain. chronic kidney disease, which could Patients may present with microscopic Describing patients from diff erent fami- indicate primary podocyte injury rather , with or without . lies, but with the same mutated amino than post-adaptive focal segmental Proteinuria may remain subnephrotic or acid residue (R702C and R702H), this glomerulosclerosis (FSGS) consequent to may become nephrotic. Th e combination paper provides genotype – phenotype cor- a reduced number of functioning neph- of glomerulopathy, sensorineural deafness, relations and makes several useful con- rons. Fift h, it suggests that MYH9 and, in some cases, may mimic tributions. First, it underscores the is expressed by podocytes and mesangial , but the other features rapidity with which chronic kidney dis- cells, as previously reported, and also by (particularly abnormal platelets and auto- ease can progress to end-stage kidney tubular cells (including proximal, loop of somal dominant mode of inheritance) disease in these patients, oft en in less Henle, and distal tubules) and endothe- should aid in the clinical distinction. than 2 – 3 years. Second, it confi rms ear- lial cells (interlobular arteries and arteri- To date, 39 MYH9 mutations, distrib- lier reports that angiotensin antagonist oles and peritubular capillaries). uted across 12 of the 40 coding exons, therapy may reduce proteinuria but does A set of overlapping syndromes, char- have been associated with ADM9 spec- not do so in all patients. Th ird, it con- acterized by macrothrombocytopenia, trum disorders (Figure 1), tabulated in a fi rms prior observations of glomerular azurophilic Dö hle-like inclusions in neu- comprehensive review. 6 Th ese include 26 trophils, sensorineural deafness, cata- missense mutations (codon changing), 1Kidney Disease Section, National Institute of racts, and glomerular injury, was linked fi ve in-frame deletions, and one dupli- Diabetes and Digestive and Kidney Diseases, to MYH9 coding region mutations (mis- cation. Also, located in the last exon, National Institutes of Health, Bethesda , sense, nonsense, and deletions) in where a truncated protein is apparently Maryland , USA 2000. 2,3 Th e most characteristic fi nding tolerated and therefore is non-lethal, are Correspondence: Jeff rey Kopp, National Institutes of Health, 10 Center Drive, Bethesda, is the macrothrombocytopenia; some two nonsense mutations (resulting in a Maryland 20892-1268, USA. patients have mild to moderate mucocu- premature stop codon) and fi ve frameshift E-mail: [email protected] taneous diathesis, but others mutations. Several individuals had

130 Kidney International (2010) 78 commentary

K835 P1927

2 11 17 22 25 26 27 31 32 38 39 41 N C

K910Q

W33C K373N R702C S1114P R1165C R1400W V1516L I1816V G1924fs P35A R702H T1155I R1165L D1424Y D1925fs T1155A N93K R705H D1424N

E1841K P1927fs D1424H

A95T Q706E E1084 del D1447H R1933fs S96L R718W D1447V R1933X D1941fs E1066_A1072 del E1066_A1072 G1055_Q1068 del G1055_Q1068

E1066_A1072 dup E1066_A1072 E1945X

Head del 092_R1162 del L1205_01207 Non-helical tail Rod

Figure 1 | Nonmuscle myosin IIA structure and MYH9 exon structure, with autosomal dominant MYH9 mutations. Above: A schematic of nonmuscle myosin IIA, showing the two heavy chains (encoded by MYH9 ) in blue (comprising 1960 amino acid residues), the two regulatory light chains in green, and the two essential light chains in orange. The head domain contains the actin-binding domain and the ATPase domain. Transition to the coiled-coil rod domain is shown at amino acid residue K835 (lysine, position 835). Transition to the non-helical extension of the rod domain occurs at P1927 (proline, position 1927). Below: MYH9 exon structure for the most typical mRNA variant, which is 7.5 kb in size and contains 41 exons. The first exon is non-coding (shown in white), and most of the 41st exon is non-coding (shown in white). Exons 2– 17 encode the head domain and are shown in gray. Exons 18– 41 encode the rod domain, shown in blue. Mutations in the non-helical tail are shown in purple. Shown are 39 MYH9 variants associated with disease. Most are mutations, but not all variants have been proven to cause disease, as some individuals have two variants and the pathogenic roles for both variants have not been established. Data from ref. 6; in that reference the coding exons are numbered from 1 to 40. Abbreviations: del, deletion; dup, duplication; fs, frameshift; X, stop codon. (Adapted from a figure graciously provided by Dr. M. Vicente-Manzanares.)

multiple mutations, and so the pathogenic (for example, the ongoing 1000 Genomes other mutations in the helical portion of is not certain. 6 As shown, 11 Project), providing insight into the fre- the rod domain. mutations occur in the head domain, and quency of rare, phenotypically silent Th e molecular mechanisms responsible the remaining mutations occur in the rod mutations across this and other genes. for the renal fi ndings in ADM9 spectrum domain of the nonmuscle myosin IIA Pecci and colleagues have presented disorders are uncertain. Nonmuscle heavy chain protein. Four residues have comprehensive data addressing geno- myosin II is expressed in nearly all cells. been aff ected by multiple missense muta- type– phenotype correlation.7 Of 93 Nonmuscle myosin IIA is normally tions: R702, R1165, D1424, and R1933. ADM9 patients, 28% manifested glomer- expressed in podocytes (at a high level, by Th is observation, together with the fre- ulopathy and 21 of 44 (48% ) evaluable immunostaining and in situ hybridization) quent occurrence of the same mutation in pedigrees had glomerulopathy. The and mesangial cells (apparently at a apparently unrelated families and in indi- mean onset age was 23 years, with 77% somewhat lower level) and, as Sekine and viduals with spontaneous mutations, sug- having onset before age 30. Of the com- colleagues suggest,1 in certain endothelial gests either that there are mutational hot monly targeted residues, R702 mutations cells and most tubular cells. Th e missense spots, or alternatively that certain residues were associated with the highest inci- mutations might be associated with haploin- are particularly important for myosin dence of glomerulopathy, with half suffi ciency, which has been shown in plate- function and substitutions are not well aff ected by age 20 and 90 % aff ected by lets with the D1424N mutation, 8 or with a tolerated. Evidence for or against the latter age 40. Strikingly, all individuals with dominant-negative phenotype, as has been may come in the near future, when wide- motor domain mutations develop shown in .9 spread use of whole-genome sequencing before age 40, while mutations Relatively few renal biopsies from makes it possible to study the sequences at 1933 in the non-helical tail were asso- ADM9 patients have been reported, of all genes, from thousands of individuals ciated with less kidney disease than perhaps in part because of the bleeding

Kidney International (2010) 78 131 commentary

Table 1 | Glomerular fi ndings from renal biopsies obtained from patients with autosomal dominant MYH9 disorders

Continental MYH9 S e r u m Light Electron Reference Age Sex descent mutation creatinine Proteinuria microscopy microscopy Epstein 13 F European R702C 0.6 mg / dl 0.2 g / d Segmental and global Not performed et al. , 197211 glomerulosclerosis, mesangial proliferation Clare 15 M European ND 1.2 mg / dl 14 g / d Endocapillary prolif- GBM thickening, et al. , 1978 19 (Mexican) eration, mesangial lamellation expansion, adhesions to Bowman’ s capsule, and moderate intersti- tial fi brosis Peterson 23 M European Not End-stage Present Pr eserved glomeruli GBM thickening, focal et al. , 1985 16 determined kidney disease with increased areas of attenuation; mesangial-cell number focal podocyte foot and matrix process eff acement T u r i et al. , 14 M European Not 0.8 mg / dl 1.6 – 4 g / d Segmental glomeru- Focal GBM thickening 1992 17 determined losclerosis and diff use and splitting, foot mesangial proliferation process eff acement Iyori et al. , 14 F Asian (Japan) Not Present Mild tubular atrophy Mesangial interposition, 1995 13 determined GBM splitting M o x e y - 7 M African Not 0.6 mg / dl 1.6 g / m2 Mild mesangial Mesangial-cell Mims, 1999 14 determined expansion proliferation and matrix expansion, GBM with variable thickening and basket-weave splitting Naito et al. , 3 F Asian (Japan) Not Not stated Present Normal GBM thickening and 1997 15 determined reticulation of the lamina densa Naito et al. , 12 F Asian (Japan) Not Normal Not stated Mesangial Partial splitting of GBM 1997 15 determined proliferation lamina densa Naito et al. , 15 M Asian (Japan) Not Not stated Nephrotic Segmental GBM thinning 1997 15 determined glomerulosclerosis Ghiggeri 49 M European D1424H 5 mg / dl Present Glomerulosclerosis Nonspecifi c et al. , 2003 12 Ghiggeri 24 F European D1424H Not stated Present Normal Focal segmental foot et al. , 200312 process eff acement Alhindawi 10 M Asian (Jordan) Not eGFR 65 ml / Present Segmental and global Not performed et al. , 2009 10 determined min / 1.73 m 2 glomerulosclerosis Yap et al. , 17 M Asian (China) R702H 2.3 mg / dl 4.5 g / d Global Not performed 2009 18 glomerulosclerosis Sekine et al. , 9 F Asian (Japan) R702C 0.4 mg / dl Present Mild mesangial-cell Mesangial-cell 2010 1 proliferation and proliferation and matrix expansion expansion, focal foot process eff acement, focal GBM thickening Sekine et al. , 11 Same case as above 0.6 mg / dl Present Segmental and global Not stated 2010 1 glomerulosclerosis Abbreviations: eGFR, estimated glomerular fi ltration rate; GBM, glomerular basement membrane. Summarized here are the glomerular fi ndings from 15 kidney biopsies obtained from 14 patients, representing all identifi ed reports of kidney biopsies obtained from patients with autosomal dominant MYH9 spectrum disorders (the diagnosis was made clinically or genetically).

diathesis. Th e reports of renal histology Nevertheless, there may be important including glomerular GBM thickening obtained from 14 ADM9 patients have lessons that can be learned. Recurring (6/ 11), splitting (6/ 11), and attenuation shown a range of fi ndings, summarized features under light microscopy include (2/ 11), so that 9 out of 11 manifested in Table 1 .1,10 – 18 To be sure, this compil- mesangial proliferation (6/ 14), segmental some abnormality of the GBM. ation may not include all published cases glomerulosclerosis (5/ 14) and variable Th ree points are worth making about and has major shortcomings: multiple tubulointerstitial disease. Recurring these pathologic findings and suggest pathologists reading the biopsies, brief features under electron microscopy, directions for future investigation to descriptions, and varied terminologies. which was reported from 11 patients, defi ne molecular mechanisms.

132 Kidney International (2010) 78 commentary

First, the frequent fi nding of mesangial Th ese GBM abnormalities raise the possi- 4 . Kopp JB , Smith MW , Nelson GW et al. MYH9 is hypercellularity is interesting; whether it is bility that the ADM9 spectrum mutations a major-effect risk gene for focal segmental glomerulosclerosis . Nat Genet 2008 ; 40 : 1175 – 1184 . due to a direct eff ect of the abnormal MYH9 disrupt the ability of the podocyte to pro- 5 . Singh N , Nainani N , Arora P et al. CKD in MYH9- protein on mesangial cells is unknown. duce extracellular matrix with the related disorders . Am J Kidney Dis 2009 ; 54 : 732 – 740 . MYH9 RNA and protein are expressed by appropriate amounts and stoichiometry or 6 . Vicente-Manzanares M , Ma X , Adelstein RS et al. Non-muscle myosin II takes centre stage in cell mesangial cells, but we have no insight into the ability to regulate the incorporation of adhesion and migration. Nat Rev Mol Cell Biol 2009 ; what pathways, direct or indirect, might these proteins into the GBM in the process 10: 778 – 790 . 7 . Pecci A , Panza E , Pujol-Moix N et al. Position of lead to proliferation. Indeed, it is not clear of physiologic remodeling. Th is is some- nonmuscle myosin heavy chain IIA (NMMHC-IIA) that infl ammatory-cell infi ltration has been what surprising, as other mutations in mutations predicts the natural history of MYH9- excluded as an explanation for the observed podocyte-expressed genes such as NPHS1 related disease . Hum Mutat 2008 ; 29 : 409 – 417 .  8 . Deutsch S , Rideau A , Bochaton-Piallat ML et al. hypercellularity. (nephrin), NPHS2 (podocin), ACTN4 ( - Asp1424Asn MYH9 mutation results in an unstable Second, fi ve biopsies showed segmen- actinin-4), and TRPC6 are not associated protein responsible for the phenotypes in May- tal glomerulosclerosis, which may be a with GBM abnormalities, and may suggest Hegglin anomaly/Fechtner syndrome. 2003 ; 102: 529 – 534 . nonspecifi c response to mesangial pro- that nonmuscle myosin IIA is particularly 9 . Pecci A , Canobbio I , Balduini A et al. Pathogenetic liferation (two of these patients also engaged in the cellular processes by which mechanisms of hematological abnormalities of showed mesangial proliferation) or to podocytes orchestrate GBM assembly and patients with MYH9 mutations. Hum Mol Genet 2005 ; 14 : 3169 – 3178 . reduced mass (one case with remodeling. 10 . Alhindawi E , Al-Jbour S . Epstein syndrome with extensive global glomerulosclerosis may In conclusion, we are just beginning to rapid progression to end stage renal disease. Saudi represent post-adaptive FSGS). Alterna- understand how MYH9 mutations and J Kidney Dis Transpl 2009 ; 20 : 1076 – 1078 . 11 . Epstein CJ , Sahud MA , Piel CF et al. Hereditary tively, FSGS may represent a manifesta- MYH9 kidney risk variants lead to such macrothrombocytopathia, nephritis and deafness. tion of podocyte injury; indeed, diverse glomerular pathology. In vitro Am J Med 1972 ; 52 : 299 – 310 . segmental podocyte foot process eff ace- studies of podocytes cultured from 12 . Ghiggeri GM , Caridi G , Magrini U et al. Genetics, clinical and pathological features of ment was present in at least three cases. ADM9 spectrum patients and MYH9 glomerulonephritis associated with mutations of Whether we label this as FSGS depends kidney risk variants, either obtained by nonmuscle myosin IIA (Fechtner syndrome). Am J on how narrowly or broadly we defi ne kidney biopsy or cultured from ,23 Kidney Dis 2003 ; 41 : 95 – 104 . 13 . Iyori H , Tokushige A , Ishitoya N et al. [A case report this diagnosis. Segmental glomeruloscle- and studies of mice that are heterozygous of Epstein syndrome] (article in Japanese). Nippon rosis can be seen in other glomerular for a MYH9 -null mutation and mice Jinzo Gakkai Shi 1995 ; 37 : 62 – 68 . 14 . Moxey-Mims MM , Young G , Silverman A et al. diseases, including IgA nephropathy, transgenic for the R702C, D1424N, and End-stage renal disease in two pediatric patients 20 with primarily mesangial pathology E1841K mutations, currently under way with Fechtner syndrome. Pediatr Nephrol 1999 ; and in membranous nephropathy, (R. Adelstein, personal communication, 13 : 782 – 786 . 15 . Naito I , Nomura S , Inoue S et al. Normal distribution although this may refl ect post-adaptive National Heart, Lung and Blood Institute, of IV in renal basement membranes in 21 FSGS. Barisoni et al. have proposed a National Institutes of Health), may shed Epstein’s syndrome . J Clin Pathol 1997 ; 50 : 919 – 922 . broad defi nition that makes room under light on these processes. 16 . Peterson LC , Rao KV , Crosson JT et al. Fechtner syndrome: a variant of Alport’s syndrome with the FSGS tent for segmental glomerulo- leukocyte inclusions and macrothrombocytopenia . sclerosis with GLA mutations (Fabry dis- DISCLOSURE Blood 1985 ; 65 : 397 – 406 . ease) and COL4 mutations (Alport The author declared no competing interests. 17 . Turi S , Kobor J , Erdos A et al. Hereditary nephritis, 22 platelet disorders and deafness —Epstein’s syndrome). ADM9 spectrum muta- syndrome. Pediatr Nephrol 1992 ; 6 : 3 8– 4 3. tions would then fi t within the subcate- ACKNOWLEDGMENTS 1 8 . Y a p D Y , T s e K C , C h a n T M et al. Epstein syndrome gory of genetic FSGS, the common This work was supported by the National presenting as renal failure in young patients. 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