Genetics of Glomerular Basement Membrane Disorders


The purpose of this review is to provide current information about glomerular disorders that arise directly from inherited abnormalities in extracellular matrix proteins intrinsic to the glomerular basement membrane (GBM) (Alport syndrome (AS), thin basement membrane nephropathy (TBMN), hereditary angiopathy associated with nephropathy, aneurysms and muscle cramps (HANAC) syndrome and Pierson syndrome), as well as disorders involving genetic defects in cellular proteins that result in structural defects in GBMs (MYH9‐related disorders, Nail–Patella syndrome, NPS). All cases of AS and approximately 50% of cases of TBMN arise from mutations affecting a type IV collagen network composed of alpha;3, α4 and α5 type IV collagen chains. The cardinal clinical feature of these disorders is hematuria. HANAC syndrome is caused by mutations that affect type IV collagen networks made up of α1 and α2 type IV collagen chains and also presents with hematuria. In contrast, Pierson syndrome, which results from mutations in the gene encoding β2 laminin, is associated with proteinuria.

Key Concepts:

  • Important physiologic qualities of the glomerular capillary wall, such as high water flux and restricted transit of proteins, rely on specific extracellular matrix proteins and their interactions with other proteins and glomerular cells.

  • Alport syndrome and thin basement membrane nephropathy (TBMN), the major genetic disorders of glomerular basement membranes (GBM), arise from abnormalities in a type IV collagen network comprising heterotrimers of α3, α4 and α5 type IV collagen chains.

  • Extrarenal features of Alport syndrome (sensorineural deafness and ocular lesions) result from abnormal type IV collagen composition of cochlear and ocular basement membranes.

  • Other inherited disorders of glomerular basement membranes result from laminin mutations (Pierson syndrome), mutations affected cytoskeletal function (MYH9‐related disorders) or dysregulation of the synthesis of extracellular matrix proteins (nail‐patella syndrome).

Keywords: glomerular basement membrane; type IV collagen; Alport syndrome; thin basement membrane nephropathy; HANAC syndrome; Nail–Patella syndrome; LMX1B; Pierson syndrome; laminin


Arrondel C, Vodovar N, Knebelmann B et al. (2002) Expression of the nonmuscle myosin heavy chain IIA in the human kidney and screening for MYH9 mutations in Epstein and Fechtner syndrome. Journal of the American Society of Nephrology 13: 65–74.

Bekheirnia MR, Reed B, Gregory MC et al. (2010) Genotype–phenotype correlation in X‐linked Alport syndrome. Journal of the American Society of Nephrology 21: 876–883.

Ben‐Bassat M, Cohen L and Rosenfeld J (1971) The glomerular basement membrane in the Nail–Patella syndrome. Archives of Pathology 92: 350–355.

Berheim J, Dechavanne M and Bryon PA (1976) Thrombocytopenia, macrothrombocytopathia, nephritis and deafness. American Journal of Medicine 61: 145–150.

Bhatt A, Broxson E, Witte D and Omoloja A (2009) Thrombocytopenia and proteinuria. Nonmuscle myosin heavy‐chain‐9‐related disease (MYH9 RD) or Epstein syndrome (ES). Pediatric Nephrology 24: 485–488.

Bongers EM, Gubler MC and Knoers NV (2002) Nail–Patella syndrome. Overview on clinical and molecular findings. Pediatric Nephrology 17: 703–712.

Bongers EM, Huysmans FT, Levtchenko E et al. (2005) Genotype–phenotype studies in Nail–Patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. European Journal of Human Genetics 13: 935–946.

Brainwood D, Kashtan C, Gubler MC and Turner AN (1998) Targets of alloantibodies in Alport anti‐glomerular basement membrane disease after renal transplantation. Kidney International 53: 762–766.

Bredrup C, Matejas V, Barrow M et al. (2008) Ophthalmological aspects of Pierson syndrome. American Journal of Ophthalmology 146: 602–611.

Cheong HI, Kashtan CE, Kim Y, Kleppel MM and Michael AF (1994) Immunohistologic studies of type IV collagen in anterior lens capsules of patients with Alport syndrome. Laboratory Investigation 70: 553–557.

Choi HJ, Lee BH, Kang JH et al. (2008) Variable phenotype of Pierson syndrome. Pediatric Nephrology 23: 243–249.

Clare NM, Montiel MM, Lifschitz MD et al. (1979) Alport's syndrome associated with macrothrombocytopenic thrombocytopenia. American Journal of Clinical Pathology 72: 111–117.

Del Pozo E and Lapp H (1970) Ultrastructure of the kidney in the nephropathy of the Nail–Patella syndrome. American Journal of Clinical Pathology 54: 845–851.

Dreyer SD, Zhou G, Baldini A et al. (1998) Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in Nail–Patella syndrome. Nature Genetics 19: 47–50.

Epstein CJ, Sahud MA, Piel CF et al. (1972) Hereditary macrothrombocytopenia, nephritis and deafness. American Journal of Medicine 52: 299–310.

Ghiggeri GM, Caridi G, Magrini U et al. (2003) Genetics, clinical and pathological features of glomerulonephritis associated with mutations of nonmuscle myosin IIA (Fechtner syndrome). American Journal of Kidney Diseases 41: 95–104.

Gross O and Kashtan CE (2009) Treatment of Alport syndrome: beyond animal models. Kidney International 76: 599–603.

Hamlington JD, Jones C and McIntosh I (2001) Twenty‐two novel LMX1B mutations identified in Nail–Patella syndrome (NPS) patients. Human Mutation 18: 458.

Hasselbacher K, Wiggins RC, Matejas V et al. (2006) Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2‐associated disorders. Kidney International 70: 1008–1012.

Hawkins CF and So E (1950) Renal dysplasia in a family with multiple hereditary abnormalities including iliac horns. Lancet I: 803–808.

Heath KE, Campos‐Barros A, Toren A et al. (2001) Nonmuscle mysoin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May–Hegglin anomaly and Fechtner, Sebastian, Epstein and Alport‐like syndromes. American Journal of Human Genetics 69: 1033–1045.

Heidet L, Bongers EM, Sich M et al. (2003) In vivo expression of putative LMX1B targets in Nail–Patella syndrome kidneys. American Journal of Pathology 163: 145–155.

Heidet L, Cohen‐Solal L, Boye E et al. (1997) Novel COL4A5/COL4A6 deletions and further characterization of the diffuse leiomyomatosis‐Alport syndrome (DL‐AS) locus define the DL critical region. Cytogenetics and Cell Genetics 78: 240–246.

Hoyer JR, Michael AF and Vernier RL (1972) Renal disease in Nail–Patella syndrome: clinical and morphologic studies. Kidney International 2: 231–238.

Jais JP, Knebelmann B, Giatras I et al. (2003) X‐linked Alport syndrome: natural history and genotype–phenotype correlations in girls and women belonging to to 195 families: a ‘European Community Alport Syndrome Concerted Action’ study. Journal of the American Society of Nephrology 14: 2603–2610.

Jais JP, Knebelmann B, Giatras I et al. (2000) X‐linked Alport syndrome: natural history in 195 families and genotype–phenotype correlations in males. Journal of the American Society of Nephrology 11: 649–657.

Jarad G, Cunningham J, Shaw AS and Miner JH (2006) Proteinuria precedes podocyte abnormalities in Lamb2–/– mice, implicating the glomerular basement membrane as an albumin barrier. Journal of Clinical Investigations 116: 2272–2279.

Kagan M, Cohen AH, Matejas V, Vlangos C and Zenker M (2008) A milder variant of Pierson syndrome. Pediatric Nephrology 23: 323–327.

Kalluri R, Shield CF, Todd P, Hudson BG and Neilson EG (1997) Isoform switching of type IV collagen is developmentally arrested in X‐linked Alport syndrome leading to increased susceptibility of renal basement membranes to endoproteolysis. Journal of Clinical Investigations 99: 2470–2478.

Kashtan CE (2006) Renal transplantation in patients with Alport syndrome. Pediatric Transplantations 10: 651–657.

Kashtan CE and Kim Y (1992) Distribution of the α1 and α2 chains of collagen IV and of collagens V and VI in Alport syndrome. Kidney International 42: 115–126.

Kashtan CE, Kim Y, Lees GE et al. (2001) Abnormal glomerular basement membrane laminins in murine, canine, and human Alport syndrome: aberrant laminin alpha2 deposition is species independent. Journal of the American Society of Nephrology 12: 252–260.

Knoers NV, Bongers EM, van Beersum SE et al. (2000) Nail–Patella syndrome: identification of mutations in the LMX1B gene in Dutch families. Journal of the American Society of Nephrology 11: 1762–1766.

Kunishima S, Matsushita T, Kojima T et al. (2001) Identification of six novel MYH9 mutations and genotype–phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. Journal of Human Genetics 46: 722–729.

Lalwani AK, Goldstein JA, Kelley MJ et al. (2000) Human nonsyndromic hereditary deafness DFNA17 is due to a mutation in nonmuscle myosin MYH9. American Journal of Human Genetics 67: 1121–1128.

Lemley KV (2009) Kidney disease in Nail–Patella syndrome. Pediatric Nephrology 24: 2345–2354.

Longo I, Porcedda P, Mari F et al. (2002) COL4A3/COL4A4 mutations: from familial hematuria to autosomal‐dominant or recessive Alport syndrome. Kidney International 61: 1947–1956.

Looij BJ, te Slaa RL, Hogewind BL and van de Kamp JJ (1988) Genetic counseling in hereditary osteo‐onychodysplasia (HOOD, Nail–Patella syndrome) with nephropathy. Journal of Medical Genetics 25: 682–686.

Marigo V, Nigro A, Pecci A et al. (2004) Correlation between the clinical phenotype of MYH9‐related disease and tissue distribution of class II nonmuscle myosin heavy chains. Genomics 83: 1125–1133.

Maselli RA, Ng JJ, Anderson JA et al. (2009) Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome. Journal of Medical Genetics 46: 203–208.

Matthews JM, Bhati M, Craig VJ et al. (2008) Competition between LIM‐binding domains. Biochemical Society Transactions 36: 1393–1397.

Meehan DT, Delimont D, Cheung L et al. (2009) Biomechanical strain causes maladaptive gene regulation, contributing to Alport glomerular disease. Kidney International 76: 968–976.

Merchant SN, Burgess BJ, Adams JC et al. (2004) Temporal bone histopathology in Alport syndrome. Laryngoscope 114: 1609–1618.

Miner JH and Sanes JR (1994) Collagen IV α3, α4 and α5 chains in rodent basal laminae: sequence, distribution, association with laminins, and developmental switches. Journal of Cell Biology 127: 879–891.

Moxey‐Mims MM, Young G, Silverman A et al. (1999) End‐stage renal disease in two pediatric patients with Fechtner syndrome. Pediatric Nephrology 13: 782–786.

Naito I, Nomura S, Inoue S et al. (1997) Normal distribution of collagen IV in renal basement membranes in Epstein's syndrome. Journal of Clinical Pathology 50: 919–922.

Noakes PG, Miner JH, Gautam M et al. (1995) The renal glomerulus of mice lacking s‐laminin/laminin β2: nephrosis despite molecular compensation by laminin β1. Nature Genetics 10: 400–406.

Ohkubo S, Takeda H, Higashide T et al. (2003) Immunohistochemical and molecular genetic evidence for type IV collagen alpha5 chain abnormality in the anterior lenticonus associated with Alport syndrome. Archives of Ophthalmology 121: 846–850.

Parsa KP, Lee DBN, Zamboni L and Glassock RJ (1976) Hereditary nephritis, deafness and abnormal thrombopoiesis: study of a new kindred. American Journal of Medicine 60: 665–671.

Pecci A, Panza E, De Rocco D et al. (2010) MYH9 related disease: four novel mutations of the tail domain of myosin‐9 correlating with a mild clinical phenotype. European Journal of Haematology 84: 291–297.

Pecci A, Panza E, Pujol‐Moix N et al. (2008) Position of nonmuscle myosin heavy chain IIA (NMMHC‐IIA) mutations predicts the natural history of MYH9‐related disease. Human Mutation 29: 409–417.

Peterson LC, Rao KV, Crosson JT and White JG (1985) Fechtner syndrome: a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopathia. Blood 65: 397–406.

Pierson M, Cordier J, Hervouuet F and Rauber G (1963) An unusual congential and familial congenital malformative combination involving the eye and kidney. Journal of Human Genetics 12: 184–213.

Plaisier E, Gribouval O, Alamowitch S et al. (2007) COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. New England Journal of Medicine 357: 2687–2695.

Pochet JM, Bobrie G, Landais P, Goldfarb B and Grunfeld J‐P (1989) Renal prognosis in Alport's and related syndromes: influence of the mode of inheritance. Nephrology Dialysis Transplantation 4: 1016–1021.

Rana K, Wang YY, Buzza M et al. (2005) The genetics of thin basement membrane nephropathy. Seminars in Nephrology 25: 163–170.

Rao VH, Lees GH, Kashtan CE et al. (2003) Increased expression of MMP‐2, MMP‐9 (type IV collagenases/gelatinases), and MT1‐MMP in canine X‐linked Alport syndrome (XLAS). Kidney International 63: 1736–1748.

Rheault MN, Kren SM, Hartich LA et al. (2010) X‐inactivation modifies disease severity in female carriers of murine X‐linked Alport syndrome. Nephrology Dialysis Transplantation 25: 764–769.

Savige J and Colville D (2009) Ocular features aid the diagnosis of Alport syndrome. Nature Reviews Nephrology 5: 356–360.

Sekine T, Konno M, Sasaki S et al. (2010) Patients with Epstein–Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease. Kidney International 78: 207–214.

Seri M, Pecci A, Di Bari F et al. (2003) 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) 82: 203–215.

Silverman ME, Goodman RM and Cuppage FE (1967) The Nail–Patella syndrome. Clinical findings and ultrastructural observations in the kidney. Archives of Internal Medicine 120: 68–74.

Sutcliffe NP, Cashman SJ, Savage CO, Fox JG and Boulton‐Jones JM (1989) Variability of the antigenicity of the glomerular basement membrane in Nail–Patella syndrome. Nephrology Dialysis Transplantation 4: 262–265.

Sweeney E, Fryer A, Mountford R, Green A and Mcintosh I (2003) Nail–Patella syndrome: review of the phenotype aided by developmental biology. Journal of Medical Genetics 40: 153–162.

Thielen BK, Barker DF, Nelson RD et al. (2003) Deletion mapping in Alport syndrome and Alport syndrome‐diffuse leiomyomatosis reveals potential mechanisms of visceral smooth muscle overgrowth. Human Mutation 22: 419.

Turi S, Kobor J, Erdos A et al. (1992) Hereditary nephritis, platelet disorders and deafness – Epstein's syndrome. Pediatric Nephrology 6: 38–43.

VanDeVoorde R, Witte D, Kogan J and Goebel J (2006) Pierson syndrome: a novel cause of congenital nephrotic syndrome. Pediatrics 118: e501–e505.

Vinge L, Lees GE, Nielsen R et al. (2010) The effect of progressive glomerular disease on megalin‐mediated endocytosis in the kidney. Nephrology Dialysis Transplantation 25: 2458–2467.

Vitelli F, Piccini M, Caroli F et al. (1999) 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 55: 335–340.

Voskarides K, Damianou L, Neocleous V et al. (2007) COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. Journal of the American Society of Nephrology 18: 3004–3016.

Witzgall R (2008) How are podocytes affected in Nail–Patella syndrome? Pediatric Nephrology 23: 1017–1020.

Zehnder AF, Adams JC, Santi PA et al. (2005) Distribution of type IV collagen in the cochlea in Alport syndrome. Archives of Otolaryngology and Head Neck Surgery 131: 1007–1013.

Zenker M, Aigner T, Wendler O et al. (2004a) Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Human Molecular Genetics 13: 2625–2632.

Zenker M, Tralau T, Lennert T et al. (2004b) Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome. American Journal of Medical Genetics A 130A: 138–145.

Zhao D, Ding J, Wang F et al. (2010) The first Chinese Pierson syndrome with novel mutations in LAMB2. Nephrology Dialysis Transplantation 25: 776–778.

Further Reading

Gubler MC (2008) Inherited diseases of the glomerular basement membrane. Nature Clinical Practice Nephrology 4: 24–37.

Kashtan CE (2011) Hereditary nephritis (Alport syndrome). In: Rose BD (ed.) UpToDate. MA: Wellesley.

Kashtan CE (2011) Thin basement membrane disease (benign familial hematuria). In: Rose BD (ed.) UpToDate. MA: Wellesley.

Kashtan CE (2011) Collagen IV‐related nephropathies (Alport syndrome and thin basement membrane nephropathy). In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews []. Seattle: University of Washington.

Miner JH (2011) Glomerular basement membrane composition and the filtration barrier. Pediatric Nephrology 26: 1413–1417.

Miner JH (2011) Organogenesis of the kidney glomerulus: focus on the glomerular basement membrane. Organogenesis 7: 75–82.

Pedchenko V, Bondar O, Fogo AB et al. (2010) Molecular architecture of the Goodpasture autoantigen in anti‐GBM nephritis. New England Journal of Medicine 363: 343–354.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Kashtan, Clifford E(Mar 2012) Genetics of Glomerular Basement Membrane Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023849]