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Idiopathic congenital central hypoventilation syndrome: Evaluation of brain-derived neurotrophic factor genomic DNA sequence variation

Authors

  • Debra E. Weese-Mayer,

    Corresponding author
    1. Department of Pediatrics, Rush Children's Hospital at Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, Illinois
    • Professor of Pediatrics at Rush University, Director, Pediatric Respiratory Medicine at Rush Children's Hospital, 1653 West Congress Parkway, Chicago, IL 60612.
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  • Stacey Bolk,

    1. Department of Genetics, Case Western Reserve University, Cleveland, Ohio
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    • a

      Dr. Chakravarti has relocated to Johns Hopkins University School of Medicine and Dr. Bolk has relocated to the Whitehead Institute at M.I.T.

  • Jean M. Silvestri,

    1. Department of Pediatrics, Rush Children's Hospital at Rush-Presbyterian-St. Luke's Medical Center, Rush University, Chicago, Illinois
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  • Aravinda Chakravarti

    1. Department of Genetics, Case Western Reserve University, Cleveland, Ohio
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    • a

      Dr. Chakravarti has relocated to Johns Hopkins University School of Medicine and Dr. Bolk has relocated to the Whitehead Institute at M.I.T.


Abstract

Idiopathic congenital central hypoventilation syndrome (CCHS) is an unique disorder of respiratory control, occurring in association with Hirschsprung disease (HSCR), tumors of neural crest origin, and symptoms of autonomic nervous system dysfunction (ANSD). CCHS is thought to be genetic in origin based upon 1) affected sib pairs, 2) genetic analysis, and 3) identification of genetic mutations in both HSCR and CCHS patients. Because these mutations have been found in but a few cases of CCHS, exploration of other candidate genes has continued. Brain-derived neurotrophic factor (BDNF) represents a potential candidate gene to consider because of altered respiratory control in the BDNF knock-out mouse model and localization to the enteric nervous system in human tissue. The objective of this study was to determine the frequency of BDNF mutations among 19 children with CCHS (five with HSCR) compared to 40 unaffected unrelated controls. Using the known genomic DNA sequence for BDNF, polymerase chain reaction (PCR)-amplified genomic DNA was analyzed by standard sequencing methods. A discrete mutation was identified in one of 19 children with isolated CCHS and the unaffected father. Specifically, an isoleucine was substituted for a threonine or serine in the amino acid sequence. Absence of this mutation in 40 controls confirmed that this mutation was likely not a common polymorphism. These data further support a genetic basis for CCHS, though mutations of BDNF are not consistent in this disorder. © 2001 Wiley-Liss, Inc.

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