TY  - CHAP
M1  - Book, Section
TI  - Transcription Factors in Eye Disease and Ocular Development
A1  - Jonathan Horsford, D.
A1  - Hanson, Isabel
A1  - Freund, Carol
A1  - McInnes, Roderick R.
A1  - van Heyningen, Veronica
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  regulation  of  cell  division,  growth,  migration,  programmed  death,  and  differentiation,  necessary  for  the  development  of  tissues  and  organs,  requires  the  ordered  activation  and  silencing  of  thousands  of  genes  in  a  spatially  and  temporally  controlled  manner.  Many  of  these  developmental  processes  are  controlled  by  tissue-specific  transcription  factors.  In  addition,  the  maintenance  of  the  differentiated  state  is  often  regulated  by  the  same  transcription  factors  required  for  formation  of  the  mature  cell.  Mutations  in  10  human  (Table  290-1)  transcription  factor  genes  have  been  shown  to  disrupt  mammalian  eye  development  or  maintenance.  Mutations  in  an  additional  18  mouse  transcription  factor  genes  have  also  been  found  to  be  associated  with  developmental  abnormalities  of  the  eye  (Table  290-2).  Human  eye  phenotypes  (Table  290-1)  can  involve  one  or  more  ocular  structures.  Developmental  anomalies  that  affect  many  parts  of  the  eye  are  termed  panocular  defects,  whereas  other  abnormalities  may  be  restricted  to  the  anterior  segment,  posterior  segment,  or  the  differentiation  or  maintenance  of  photoreceptors.Panocular  defects  are  broad  phenotypes  that  arise  by  at  least  two  different  general  mechanisms.  The  first,  best  illustrated  by  heterozygous  mutations  in  the  paired/homeobox  gene  PAX6,  reflects  the  fact  that  the  gene  is  expressed  in  and  required  for  the  normal  development  and/or  maintenance  of  all  regions  of  the  developing  eye:  both  neural  and  pigmented  retina,  iris,  lens,  and  surface  ectoderm  (Fig.  290-2).  Thus,  PAX6  mutations  cause  panocular  disease  in  the  sense  that  many  different  parts  of  the  eye  may  be  affected,  although  in  many  patients  only  one  region  is  predominantly  abnormal.  The  second  mechanism  by  which  panocular  defects  arise  reflects  the  fact  that  a  gene  expressed  in  one  region  of  the  developing  eye  may  nevertheless  be  essential,  via  secondary  physiological  processes,  for  the  normal  development  of  other  ocular  structures.  This  mechanism  is  illustrated  by  the  abnormalities  that  result  from  mutations  in  the  CHX10  homeobox  gene  because,  at  least  in  the  two  patients  identified  to  date,  the  eye  is  small  and  many  structures  are  abnormal,  even  though  the  developmental  expression  of  CHX10  in  the  eye  is  restricted  solely  to  the  progenitor  cells  of  the  neuroretina.PAX6,  mapping  to  chromosome  11p13,  is  a  transcription  factor  with  both  a  paired-  and  a  homeodomain.  It  is  mutated  in  aniridia  and  related  anomalies.  Most  aniridia  mutations  lead  to  premature  protein  truncations,  and  haploinsufficiency.  Cases  classified  as  aniridia  always  have  severe  iris  hypoplasia  and  usually  one  or  more  of  the  following  features:  foveal/macular  hypoplasia,  cataracts,  glaucoma,  and  corneal  limbal  insufficiency,  making  this  a  panocular  and  progressive  developmental  disease.  More  infrequently  (<10  percent  of  cases  analyzed)  missense  mutations  are  seen.  Foveal  hypoplasia,  Peters  anomaly,  corectopia  and  cataracts  have  been  observed  in  these  amino  acid  substitution  cases.  These  “variant”  phenotypes  usually  have  less  severe  or  no  iris  involvement.  The  universal  involvement  of  PAX6  in  the  development  of  the  eye  in  species  ranging  from  Drosophila  to  humans  serves  as  a  paradigm  for  wide-ranging  evolutionary  conservation  of  key  developmental  regulators.  This  concept  allows  us  to  use  a  broad  range  of  model  organisms  to  understand  gene  function  and  define  interacting  developmental  pathways.  Although  there  is  no  reduction  in  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/17
UR  - ommbid.mhmedical.com/content.aspx?aid=1184071293
ER  -