RT Book, Section
A1 Gharavi, Ali
A1 Lifton, Richard P.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181476346
T1 The Inherited Basis of Blood Pressure Variation and Hypertension
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=1181476346
RD 2024/04/18
AB Blood  pressure  is  a  multifactorial  quantitative  trait  showing  a  continuous  distribution  in  the  general  population.  The  determinants  of  blood  pressure  variation  include  genetic  and  environmental  factors,  as  well  as  demographic  factors  such  as  age,  gender,  and  ethnicity.  Multiple  lines  of  evidence  demonstrate  the  importance  of  heredity  in  blood  pressure  variation.  Blood  pressure  aggregates  within  families,  with  greater  concordance  in  biologic  sibs  than  in  adoptive  sibs  living  in  the  same  household.  Monozygotic  twins  who  share  100  percent  of  their  genes  show  significantly  greater  concordance  in  blood  pressure  than  do  dizygotic  twins  who  only  share  50  percent  of  their  genes.  The  impact  of  genetic  factors  on  the  development  of  hypertension  is  modified  by  environmental  factors  such  as  weight  gain  and  sodium  intake.Blood  pressure  is  regulated  by  the  interplay  between  a  large  number  of  physiological  variables.  Physiological  studies  have  not  generally  succeeded  in  identifying  the  initiating  factors  responsible  for  the  development  of  high  blood  pressure.  However,  these  studies  indicate  that  the  kidney  plays  an  essential  role  in  the  long-term  regulation  of  blood  pressure.  Maintenance  of  elevated  blood  pressure  implicates  a  derangement  in  the  renal  pressure  natriuresis  mechanism,  and  disturbance  in  this  system  has  been  verified  in  humans  with  essential  hypertension  as  well  as  in  experimental  models  of  the  disease.  At  steady  state,  hypertension  is  characterized  by  a  rightward  resetting  of  the  pressure  natriuresis  response,  resulting  in  inappropriately  elevated  blood  volume  for  the  level  of  blood  pressure.  This  signifies  that  derangements  in  salt  handling  are  likely  to  participate  in  the  development  of  hypertension.  Genetic  studies  confirm  these  findings  and  demonstrate  that  mutations  underlying  all  Mendelian  forms  of  high  and  low  blood  pressure  converge  on  a  final  common  pathway:  mutations  that  cause  a  net  increase  in  salt  reabsorption  result  in  hypertension,  whereas  mutations  that  cause  salt  wasting  produce  hypotension.Mendelian  forms  of  hypertension:  Glucocorticoid-remediable  aldosteronism  is  caused  by  unequal  crossing  over,  fusing  regulatory  sequences  of  the  11-beta  hydroxylase  onto  coding  sequences  of  the  aldosterone  synthase  genes,  resulting  in  ectopic  production  of  aldosterone  under  the  control  of  ACTH.  Liddle  syndrome  is  caused  by  activating  mutations  in  genes  encoding  the  beta  and  gamma  subunits  of  the  epithelial  sodium  channel  in  the  distal  nephron,  leading  to  increased  distal  sodium  reabsorption.  Apparent  mineralocorticoid  excess  is  caused  by  11-beta  hydroxysteroid  dehydrogenase  deficiency  that  results  in  excessive  stimulation  of  the  mineralocorticoid  receptor  by  cortisol.  Activating  mutations  in  the  mineralocorticoid  receptor  cause  hypertension  with  marked  exacerbation  during  pregnancy.  The  hypertensive  forms  of  congenital  adrenal  hyperplasia  are  caused  by  enzyme  deficiencies  in  the  steroid  synthesis  pathways  that  lead  to  accumulation  of  mineralocorticoid  precursors.  Finally,  pseudohypoaldosteronism  type  II,  characterized  by  hypertension  and  hyperkalemia,  and  the  syndrome  of  hypertension  with  brachydactyly  are  two  Mendelian  disorders  that  have  been  mapped  but  whose  molecular  etiologies  have  not  yet  been  defined.Mendelian  forms  of  hypotension:  Pseudohypoaldosteronism  type  I  features  renal  salt  wasting  with  impaired  secretion  of  potassium  and  hydrogen  ions.  Recessive  and  dominant  PHA-I  are  caused  by  loss-of-function  mutations  in  the  genes  encoding  subunits  of  the  epithelial  sodium  channel  and  the  mineralocorticoid  receptor,  respectively.  Congenital  adrenal  hyperplasia  with  salt  wasting  caused  by  ...