RT Book, Section
A1 Antonarakis, Stylianos E.
A1 Krawczak, Michael
A1 Cooper, David N.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181402391
T1 The Nature and Mechanisms of Human Gene Mutation
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=1181402391
RD 2024/04/23
AB There  are  a  variety  of  different  types  of  mutations  in  the  human  genome  and  many  diverse  mechanisms  for  their  generation.Single-base-pair  substitutions  account  for  the  majority  of  gene  defects.  Among  them,  the  hypermutability  of  CpG  dinucleotides  represents  the  most  important  and  frequent  cause  of  mutation  in  humans.Point  mutations  may  affect  transcription  and  translation,  as  well  as  mRNA  splicing  and  processing.  Mutations  in  regulatory  elements  are  of  particular  significance,  since  they  often  reveal  the  existence  of  DNA  domains  that  are  bound  by  regulatory  proteins.  Similarly,  mutations  that  affect  mRNA  splicing  can  contribute  to  our  understanding  of  the  splicing  mechanism.We  describe  mechanisms  of  gene  deletion  and  the  DNA  sequences  that  may  predispose  to  such  lesions,  as  well  as  potential  mechanisms  underlying  insertions,  duplications,  or  inversions,  with  representative  examples.Retrotransposition  is  a  rare  but  biologically  fascinating  phenomenon  that  can  lead  to  abnormal  phenotypes  if  the  double-stranded  DNA  is  inserted  in  functionally  important  regions  of  a  gene.  Long  interspersed  repeat  elements  (LINEs)  and  Alu  repetitive  elements  and  pseudogenes  have  been  shown  to  function  as  retrotransposons,  and  their  de  novo  insertion  in  the  genome  can  produce  disease.The  expansion  of  trinucleotide  repeats  represents  a  relatively  novel  category  of  mutations  in  humans.  There  is  a  growing  list  of  disorders  that  result  from  an  abnormal  copy  number  of  trinucleotides  within  the  5′  or  3′  untranslated  regions,  coding  sequences,  and  introns  of  genes.  The  pathophysiologic  effects  of  the  expansion  of  the  trinucleotide  repeat  are  unknown.  Additionally,  at  least  one  disorder  is  caused  by  expansion  of  a  12mer  repeat  (progressive  myoclonus  epilepsy).The  study  of  mutations  in  human  genes  is  of  paramount  importance  in  understanding  the  pathophysiology  of  hereditary  disorders,  in  providing  improved  diagnostic  tests,  and  in  designing  appropriate  therapeutic  approaches.