TY  - CHAP
M1  - Book, Section
TI  - The GM2 Gangliosidoses
A1  - Gravel, Roy A.
A1  - Kaback, Michael M.
A1  - Proia, Richard L.
A1  - Sandhoff, Konrad
A1  - Suzuki, Kinuko
A1  - Suzuki, Kunihiko
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - The  GM2  gangliosidoses  are  a  group  of  inherited  disorders  caused  by  excessive  accumulation  of  ganglioside  GM2  and  related  glycolipids  in  the  lysosomes,  mainly  of  neuronal  cells.  The  enzymatic  hydrolysis  of  ganglioside  GM2  requires  that  it  be  complexed  with  a  substrate-specific  cofactor,  the  GM2  activator.  There  are  two  isoenzymes  of  β-hexosaminidase,  Hex  A,  structure  αβ,  and  Hex  B,  structure  ββ  where  only  Hex  A  can  act  on  the  ganglioside  GM2/GM2  activator  complex.  Defects  in  any  of  three  genes  may  lead  to  GM2  gangliosidosis:  HEXA,  which  encodes  the  α-subunit  of  Hex  A;  HEXB,  which  encodes  the  β-subunit  of  Hex  A  and  Hex  B;  or  GM2A,  which  encodes  the  monomeric  GM2  activator.  There  are  three  forms  of  GM2  gangliosidosis:  (a)  Tay-Sachs  disease  and  variants,  resulting  from  mutations  of  the  HEXA  gene,  are  associated  with  deficient  activity  of  Hex  A  but  normal  Hex  B;  (b)  Sandhoff  disease  and  variants,  resulting  from  mutations  of  the  HEXB  gene,  are  associated  with  deficient  activity  of  both  Hex  A  and  Hex  B;  and  (c)  GM2  activator  deficiency,  due  to  mutation  of  the  GM2A  gene,  is  characterized  by  normal  Hex  A  and  Hex  B  but  the  inability  to  form  a  functional  ganglioside  GM2/GM2  activator  complex.  There  are  also  pseudodeficient  or  clinically  benign  “disorders”  characterized  by  biochemical  defects  of  Hex  A  but  functional  activity  toward  ganglioside  GM2.  The  gross  pathology  is  very  similar  in  Tay-Sachs  disease,  Sandhoff  disease  and  GM2  activator  deficiency,  except  that  there  is  also  involvement  of  the  visceral  organs  in  Sandhoff  disease.  The  most  pronounced  cellular  change  is  the  presence  of  swollen  neurons  with  storage  material  in  lysosomes  throughout  the  nervous  system.  Characteristic  inclusions  are  the  so-called  membranous  cytoplasmic  bodies.The  hexosaminidases  and  GM2  activator  are  glycoproteins  that  are  synthesized  in  the  lumen  of  the  endoplasmic  reticulum  (ER)  and  processed  through  the  Golgi.  They  are  transported  to  the  lysosome  via  the  mannose-6-phosphate  receptor  where  they  are  processed  further  to  their  final  “mature”  forms.  β-hexosaminidase  A  (Hex  A)  and  β-hexosaminidase  B  (Hex  B)  hydrolyze  a  broad  spectrum  of  substrates  that  are  specific  for  terminal  GlcNAc  or  GalNAc  residues  in  β-linkage.  Active  site  residues  and  the  mechanism  of  catalysis  are  being  revealed  through  mutagenesis,  photoaffinity  labeling  with  substrate  analogs,  and  studies  of  chimeric  α-β  enzyme.  In  addition  to  the  hydrolysis  of  ganglioside  GM2  by  only  Hex  A,  both  isoenzymes  will  catabolize  glycoproteins,  glycosaminoglycans,  and  glycolipids.  They  will  also  hydrolyze  synthetic  substrates  of  which  the  most  sensitive  and  commonly  used  is  β-GlcNAc  derivative  of  4-methylumbelliferone  (4MUG).  It  is  recognized  by  both  Hex  A  and  Hex  B  and  does  not  require  the  GM2  activator.  Using  4MUG,  Hex  A  and  Hex  B  can  be  distinguished  by  taking  advantage  of  different  thermal  or  other  characteristics  of  the  isoenzymes.  A  related  compound  cleaved  by  Hex  A  (and  Hex  S),  but  not  Hex  B,  is  4-methylumbelliferyl-GlcNAc-6-sulfate  (4MUGS).  Substrate  such  as  4MUG  or  4MUGS  are  used  for  routine  diagnostic  testing  and  for  screening  of  carriers  of  the  gene  encoding  the  α-subunit  of  Hex  A  isoenzyme  in  humans  (HEXA)  or  the  gene  encoding  the  β-subunit  of  Hex  A  and  Hex  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/19
UR  - ommbid.mhmedical.com/content.aspx?aid=1181467110
ER  -