RT Book, Section
A1 Karl, Tryggvason
A1 Martin, Paula
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181476633
T1 Alport Syndrome and Basement Membrane Collagen
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181476633
RD 2024/04/17
AB Alport  syndrome  is  a  progressive  hereditary  kidney  disease  characterized  by  hematuria,  and  often  associated  with  extrarenal  complications,  such  as  sensorineural  hearing  loss  and  ocular  abnormalities.  By  electron  microscopy  ultrastructural  changes,  including  thinning,  thickening,  and  splitting,  can  be  seen  in  the  glomerular  basement  membrane  (GBM).  Alport  syndrome  is  mainly  inherited  as  an  X-linked  dominant  trait  (MIM  301050)  with  mutations  in  the  type  IV  collagen  α5  chain  gene  (COL4A5),  but  both  autosomal  recessive  (MIM  203780)  and  dominant  forms  also  exist.  Autosomal  Alport  syndrome  is  caused  by  mutations  in  the  COL4A3  and  COL4A4  genes  encoding  the  type  IV  collagen  α3  and  α4  chains,  respectively.  Additionally,  numerous  deletions  involving  the  5′  ends  of  both  the  COL4A6  gene  and  the  adjacent  COL4A5  gene  have  been  reported  to  cause  a  rare  disorder,  diffuse  leiomyomatosis,  that  is  associated  with  Alport  syndrome  (MIM  308940,  303631).  A  minority  of  Alport  syndrome  patients  develop  anti-GBM  nephritis  involving  the  transplanted  allograft.Basement  membranes  are  thin,  extracellular,  sheet-like  structures  that  separate  cells  of  organized  tissues  from  the  interstitial  connective  tissue.  The  major  complications  of  Alport  syndrome—hematuria  and  proteinuria—are  caused  by  structural  alterations  and  consequent  malfunction  of  the  glomerular  filtration  barrier,  especially  glomerular  basement  membrane,  a  major  component  of  the  glomerular  filtration  barrier.  The  molecular  structure  of  the  GBM  is  much  the  same  as  that  of  basement  membranes  in  other  tissues.  The  major  structural  component  is  type  IV  collagen  that  forms  a  tightly  cross-linked  network  in  which  a  less  dense  laminin  network  is  connected  via  entactin  (nidogen)  molecules.Different  triple-helical  type  IV  collagen  molecules  are  composed  of  six  genetically  distinct  α-chains,  namely  α1(IV),  α2(IV),  α3(IV),  α4(IV),  α5(IV),  or  α6(IV).  Each  type  IV  collagen  α-chain  contains  a  long  collagenous  domain,  a  short  noncollagenous  N-terminus,  and  a  noncollagenous  domain  (NC1)  at  the  C-terminus.  Type  IV  collagen  molecules  self-assemble  into  a  complex  network  structure  via  C-terminal  NC1  domains  forming  dimers,  and  at  the  N-termini  forming  tetramers.  The  molecular  composition  of  different  type  IV  collagen  networks  varies  from  tissue  to  tissue.Type  IV  collagen  genes  are  very  large,  the  smallest  one  having  46  exons.  An  interesting  feature  is  that  the  six  genes  are  located  pair-wise  in  three  different  chromosomes,  sharing  a  common  bidirectional  promoter.About  300  mutations  have  been  reported  in  Alport  syndrome  patients  in  the  COL4A3,  COL4A4,  and  COL4A5  genes.  Different  mutations  cause  different  phenotypes,  but  it  is  difficult  to  predict  the  consequences  of  a  certain  mutation,  because  deletion  of  a  whole  gene  does  not  necessarily  produce  a  more  severe  phenotype  than  does  an  amino  acid  substitution.  Immunohistologic  studies  of  tissues  from  Alport  syndrome  patients  demonstrate  the  existence  of  different  α-chain  networks  in  different  tissues.  Thus,  differential  pattern  of  staining  in  skin  sections  may  be  used  to  distinguish  between  X-linked  and  autosomal  recessive  forms  of  Alport  syndrome.Alport  syndrome,  which  primarily  affects  the  renal  glomeruli,  is  an  attractive  disease  target  for  gene  therapy.