This review provides current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (Alport syndrome, thin basement membrane nephropathy, HANAC syndrome and Pierson syndrome). The authors also discuss disorders involving genetic defects in cellular proteins that result in structural defects in glomerular basement membranes (MYH9-related disorders, nail-patella syndrome).

Keywords:
HANAC syndrome, Pierson syndrome, MYH9-related diseases, Nail-patella syndrome, Glomerular basement membrane, Alport syndrome, Thin basement membrane nephropathy
1.
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer K-O, Flinter F, Pirson Y, Verellen C, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Krejcova S, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC: X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 2000;11:649–657.
2.
Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, Weber M, Gross O, Netzer KO, Flinter F, Pirson Y, Dahan K, Wieslander J, Persson U, Tryggvason K, Martin P, Hertz JM, Schroder C, Sanak M, Carvalho MF, Saus J, Antignac C, Smeets H, Gubler MC: X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a ‘European Community Alport Syndrome Concerted Action’ study. J Am Soc Nephrol 2003;14:2603–2610.
3.
Pochet JM, Bobrie G, Landais P, Goldfarb B, Grunfeld J-P: Renal prognosis in Alport’s and related syndromes: influence of the mode of inheritance. Nephrol Dial Transpl 1989;4:1016–1021.
4.
Kashtan CE, Kim Y: Distribution of the a1 and a2 chains of collagen IV and of collagens V and VI in Alport syndrome. Kidney Int 1992;42:115–126.
5.
Kalluri R, Shield CF, Todd P, Hudson BG, Neilson EG: Isoform switching of type IV collagen is developmentally arrested in X-linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. J Clin Invest 1997;99:2470–2478.
6.
Kashtan CE, Kim Y, Lees GE, Thorner PS, Virtanen I, Miner JH: Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: aberrant laminin alpha2 deposition is species independent. J Am Soc Nephrol 2001;12:252–260.
7.
Abrahamson DR, Prettyman AC, Robert B, St John PL: Laminin-1 reexpression in Alport mouse glomerular basement membranes. Kidney Int 2003;63:826–834.
8.
Rheault MN, Kren SM, Hartich LA, Wall M, Thomas W, Mesa HA, Avner P, Lees GE, Kashtan CE, Segal Y: X-inactivation modifies disease severity in female carriers of murine X-linked Alport syndrome. Nephrol Dial Transplant 2010;25:764–769.
9.
Heidet L, Cohen-Solal L, Boye E, Thorner P, Kemper MJ, David A, Larget Piet L, Zhou J, Flinter F, Zhang X, Gubler MC, Antignac C: Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis-Alport syndrome (DL-AS) locus define the DL critical region. Cytogenet Cell Genet 1997;78:240–246.
10.
Thielen BK, Barker DF, Nelson RD, Zhou J, Kren SM, Segal Y: Deletion mapping in Alport syndrome and Alport syndrome- diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth. Hum Mutat 2003;22:419.
11.
Vitelli F, Piccini M, Caroli F, Franco B, Malandrini A, Pober B, Jonsson J, Sorrentino V, Renieri A: Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome. Genomics 1999;55:335–340.
12.
Rana K, Wang YY, Buzza M, Tonna S, Zhang KW, Lin T, Sin L, Padavarat S, Savige J: The genetics of thin basement membrane nephropathy. Semin Nephrol 2005;25:163–170.
13.
Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P: COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med 2007;357:2687–2695.
14.
Zenker M, Aigner T, Wendler O, Tralau T, Muntefering H, Fenski R, Pitz S, Schumacher V, Royer-Pokora B, Wuhl E, Cochat P, Bouvier R, Kraus C, Mark K, Madlon H, Dotsch J, Rascher W, Maruniak-Chudek I, Lennert T, Neumann LM, Reis A: Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 2004;13:2625–2632.
15.
Pierson M, Cordier J, Hervouuet F, Rauber G: An unusual congential and familial congenital malformative combination involving the eye and kidney (in French). J Genet Hum 1963;12:184–213.
16.
Zenker M, Tralau T, Lennert T, Pitz S, Mark K, Madlon H, Dotsch J, Reis A, Muntefering H, Neumann LM: Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome. Am J Med Genet A 2004;130A:138–145.
17.
Choi HJ, Lee BH, Kang JH, Jeong HJ, Moon KC, Ha IS, Yu YS, Matejas V, Zenker M, Choi Y, Cheong HI: Variable phenotype of Pierson syndrome. Pediatr Nephrol 2008.
18.
Kagan M, Cohen AH, Matejas V, Vlangos C, Zenker M: A milder variant of Pierson syndrome. Pediatr Nephrol 2008;23:323–327.
19.
Bredrup C, Matejas V, Barrow M, Blahova K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendonca EL, Kagan M, Koenig J, Krastel H, Kroes HY, Saggar A, Sawyer T, Schittkowski M, Swietlinski J, Thompson D, VanDeVoorde RG, Wittebol-Post D, Woodruff G, Zurowska A, Hennekam RC, Zenker M, Russell-Eggitt I: Ophthalmological aspects of Pierson syndrome. Am J Ophthalmol 2008;146:602–611.
20.
Hasselbacher K, Wiggins RC, Matejas V, Hinkes BG, Mucha B, Hoskins BE, Ozaltin F, Nurnberg G, Becker C, Hangan D, Pohl M, Kuwertz-Broking E, Griebel M, Schumacher V, Royer-Pokora B, Bakkaloglu A, Nurnberg P, Zenker M, Hildebrandt F: Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int 2006;70:1008–1012.
21.
Maselli RA, Ng JJ, Anderson JA, Cagney O, Arredondo J, Williams C, Wessel HB, Abdel-Hamid H, Wollmann RL: Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. J Med Genet 2009;46:203–208.
22.
Miner JH, Sanes JR: Collagen IV a3, a4 and a5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches. J Cell Biol 1994;127:879–891.
23.
VanDeVoorde R, Witte D, Kogan J, Goebel J: Pierson syndrome: a novel cause of congenital nephrotic syndrome. Pediatrics 2006;118:e501–e505.
24.
Zhao D, Ding J, Wang F, Fan Q, Guan N, Wang S, Zhang Y: The first Chinese Pierson syndrome with novel mutations in LAMB2. Nephrol Dial Transplant 2010;25:776–778.
25.
Jarad G, Cunningham J, Shaw AS, Miner JH: Proteinuria precedes podocyte abnormalities in Lamb2–/– mice, implicating the glomerular basement membrane as an albumin barrier. J Clin Invest 2006;116:2272–2279.
26.
Noakes PG, Miner JH, Gautam M, Cunningham JM, Sanes JR, Merlie JP: The renal glomerulus of mice lacking s-laminin/laminin b2: nephrosis despite molecular compensation by laminin b1. Nat Genet 1995;10:400–406.
27.
Seri M, Pecci A, Di Bari F, Cusano R, Savino M, Panza E, Nigro A, Noris P, Gangarossa S, Rocca B, Gresele P, Bizzaro N, Malatesta P, Koivisto PA, Longo I, Musso R, Pecoraro C, Iolascon A, Magrini U, Rodriguez Soriano J, Renieri A, Ghiggeri GM, Ravazzolo R, Balduini CL, Savoia A: MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness. Medicine (Baltimore) 2003;82:203–215.
28.
Berheim J, Dechavanne M, Bryon PA, Lagarde M, Colon S, Pozet N, Traeger J: Thrombocytopenia, macrothrombocytopathia, nephritis and deafness. Am J Med 1976;61:145–150.
29.
Epstein CJ, Sahud MA, Piel CF, Goodman JR, Bernfield MR, Kushner JH, Ablin AR: Hereditary macrothrombocytopenia, nephritis and deafness. Am J Med 1972;52:299–310.
30.
Parsa KP, Lee DBN, Zamboni L, Glassock RJ: Hereditary nephritis, deafness and abnormal thrombopoiesis: study of a new kindred. Am J Med 1976;60:665–671.
31.
Peterson LC, Rao KV, Crosson JT, White JG: Fechtner syndrome: a variant of Alport’s syndrome with leukocyte inclusions and macrothrombocytopathia. Blood 1985;65:397–406.
32.
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: Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome). Am J Kidney Dis 2003;41:95–104.
33.
Heath KE, Campos-Barros A, Toren A, Rezenfeld-Granot G, Carlsson LE, Savige J, Denison JC, Gregory MC, White JG, Barker DF, Greinacher A, Epstein CJ, Glucksman MJ, Martignetti JA: Nonmuscle mysoin heavy chain IIA mutations define a spectrum of autosmal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein and Alport-like syndromes. Am J Hum Genet 2001;69:1033–1045.
34.
Kunishima S, Matsushita T, Kojima T, Amemiya N, Choi YM, Hosaka N, Inoue M, Jung Y, Mamiya S, Matsumoto K, Miyajima Y, Zhang G, Ruan C, Saito K, Song KS, Yoon HJ, Kamiya T, Saito H: Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. J Hum Genet 2001;46:722–729.
35.
Pecci A, Panza E, Pujol-Moix N, Klersy C, Di Bari F, Bozzi V, Gresele P, Lethagen S, Fabris F, Dufour C, Granata A, Doubek M, Pecoraro C, Koivisto PA, Heller PG, Iolascon A, Alvisi P, Schwabe D, De Candia E, Rocca B, Russo U, Ramenghi U, Noris P, Seri M, Balduini CL, Savoia A: Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. Hum Mutat 2008;29:409–417.
36.
Moxey-Mims MM, Young G, Silverman A, Selby DM, White JG, Kher KK: End-stage renal disease in two pediatric patients with Fechtner syndrome. Pediatr Nephrol 1999;13:782–786.
37.
Sekine T, Konno M, Sasaki S, Moritani S, Miura T, Wong WS, Nishio H, Nishiguchi T, Ohuchi MY, Tsuchiya S, Matsuyama T, Kanegane H, Ida K, Miura K, Harita Y, Hattori M, Horita S, Igarashi T, Saito H, Kunishima S: Patients with Epstein-Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease. Kidney Int 2010;78:207–214.
38.
Lalwani AK, Goldstein JA, Kelley MJ, Luxford W, Castelein CM, Mhatre AN: Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. Am J Hum Genet 2000;67:1121–1128.
39.
Clare NM, Montiel MM, Lifschitz MD, Bannayan GA: Alport’s syndrome associated with macrothrombocytopenic thrombocytopenia. Am J Clin Pathol 1979;72:111–117.
40.
Turi S, Kobor J, Erdos A, Bodrogi T, Virag I, Ormos J: Hereditary nephritis, platelet disorders and deafness-Epstein’s syndrome. Pediatr Nephrol 1992;6:38–43.
41.
Bhatt A, Broxson E, Witte D, Omoloja A: Thrombocytopenia and proteinuria. Nonmuscle myosin heavy-chain-9-related disease (MYH9 RD) or Epstein syndrome (ES). Pediatr Nephrol 2009;24:485–488.
42.
Naito I, Nomura S, Inoue S, Kagawa M, Kawai S, Gunshin Y, Joh K, Tsukidate C, Sado Y, Osawa G: Normal distribution of collagen IV in renal basement membranes in Epstein’s syndrome. J Clin Pathol 1997;50:919–922.
43.
Arrondel C, Vodovar N, Knebelmann B, Grunfeld JP, Gubler MC, Antignac C, Heidet L: Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndrome. J Am Soc Nephrol 2002;13:65–74.
44.
Marigo V, Nigro A, Pecci A, Montanaro D, Di Stazio M, Balduini CL, Savoia A: Correlation between the clinical phenotype of MYH9-related disease and tissue distribution of class II nonmuscle myosin heavy chains. Genomics 2004;83:1125–1133.
45.
Pecci A, Panza E, De Rocco D, Pujol-Moix N, Girotto G, Podda L, Paparo C, Bozzi V, Pastore A, Balduini CL, Seri M, Savoia A: MYH9 related disease: four novel mutations of the tail domain of myosin-9 correlating with a mild clinical phenotype. Eur J Haematol 2010;84:291–297.
46.
Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA: MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 2008;40:1175–1184.
47.
Kao WH, Klag MJ, Meoni LA, Reich D, Berthier-Schaad Y, Li M, Coresh J, Patterson N, Tandon A, Powe NR, Fink NE, Sadler JH, Weir MR, Abboud HE, Adler SG, Divers J, Iyengar SK, Freedman BI, Kimmel PL, Knowler WC, Kohn OF, Kramp K, Leehey DJ, Nicholas SB, Pahl MV, Schelling JR, Sedor JR, Thornley-Brown D, Winkler CA, Smith MW, Parekh RS: MYH9 is associated with nondiabetic end-stage renal disease in African Americans. Nat Genet 2008;40:1185–1192.
48.
Mino RA, Mino VH, Livingstone RG: Osseous dysplasia and dystrophy of the nail: review of the literature and report of a case. Am J Roentgenol 1948;6:633–641.
49.
Hawkins CF, Smith OE: Renal dysplasia in a family with multiple hereditary abnormalities including iliac horns. Lancet 1950;i:803–808.
50.
Lemley KV: Kidney disease in nail-patella syndrome. Pediatr Nephrol 2009;24:2345–2354.
51.
Sweeney E, Fryer A, Mountford R, Green A, McIntosh I: Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003;40:153–162.
52.
Looij BJ Jr, te Slaa RL, Hogewind BL, van de Kamp JJ: Genetic counselling in hereditary osteo-onychodysplasia (HOOD, nail-patella syndrome) with nephropathy. J Med Genet 1988;25:682–686.
53.
Bongers EM, Gubler MC, Knoers NV: Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002;17:703–712.
54.
Ben-Bassat M, Cohen L, Rosenfeld J: The glomerular basement membrane in the nail-patella syndrome. Arch Pathol 1971;92:350–355.
55.
Del Pozo E, Lapp H: Ultrastructure of the kidney in the nephropathy of the nail-patella syndrome. Am J Clin Pathol 1970;54:845–851.
56.
Hoyer JR, Michael AF, Vernier RL: Renal disease in nail-patella syndrome: clinical and morphologic studies. Kidney Int 1972;2:231–238.
57.
Silverman ME, Goodman RM, Cuppage FE: The Nail-Patella syndrome. Clinical findings and ultrastructural observations in the kidney. Arch Intern Med 1967;120:68–74.
58.
Heidet L, Bongers EM, Sich M, Zhang SY, Loirat C, Meyrier A, Broyer M, Landthaler G, Faller B, Sado Y, Knoers NV, Gubler MC: In vivo expression of putative LMX1B targets in nail-patella syndrome kidneys. Am J Pathol 2003;163:145–155.
59.
Sutcliffe NP, Cashman SJ, Savage CO, Fox JG, Boulton-Jones JM: Variability of the antigenicity of the glomerular basement membrane in nail-patella syndrome. Nephrol Dial Transplant 1989;4:262–265.
60.
Matthews JM, Bhati M, Craig VJ, Deane JE, Jeffries C, Lee C, Nancarrow AL, Ryan DP, Sunde M: Competition between LIM-binding domains. Biochem Soc Trans 2008;36:1393–1397.
61.
Witzgall R: How are podocytes affected in nail-patella syndrome? Pediatr Nephrol 2008;23:1017–1020.
62.
Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, Johnson RL, Lee B: Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 1998;19:47–50.
63.
Hamlington JD, Jones C, McIntosh I: Twenty-two novel LMX1B mutations identified in nail patella syndrome (NPS) patients. Hum Mutat 2001;18:458.
64.
Knoers NV, Bongers EM, van Beersum SE, Lommen EJ, van Bokhoven H, Hol FA: Nail-patella syndrome: identification of mutations in the LMX1B gene in Dutch families. J Am Soc Nephrol 2000;11:1762–1766.
65.
Bongers EM, Huysmans FT, Levtchenko E, de Rooy JW, Blickman JG, Admiraal RJ, Huygen PL, Cruysberg JR, Toolens PA, Prins JB, Krabbe PF, Borm GF, Schoots J, van Bokhoven H, van Remortele AM, Hoefsloot LH, van Kampen A, Knoers NV: Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet 2005;13:935–946.
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2010
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