A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects

Science. 1999 Feb 19;283(5405):1158-61. doi: 10.1126/science.283.5405.1158.

Abstract

Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of UFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Comment

MeSH terms

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Aorta, Thoracic / abnormalities
  • Aorta, Thoracic / embryology
  • Aorta, Thoracic / metabolism
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins / genetics
  • Chromosomes, Human, Pair 22 / genetics*
  • Craniofacial Abnormalities / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Embryo, Mammalian / metabolism
  • Gene Deletion*
  • Gene Expression Regulation, Developmental
  • Heart / embryology
  • Heart Defects, Congenital / genetics*
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Neural Crest / cytology
  • Neural Crest / embryology
  • Phenotype
  • Proteins / genetics*
  • Proteins / physiology
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Ubiquitins / metabolism
  • Zebrafish Proteins

Substances

  • Adaptor Proteins, Vesicular Transport
  • Basic Helix-Loop-Helix Transcription Factors
  • CDC45 protein, human
  • Cdc45 protein, mouse
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • HAND2 protein, human
  • Hand2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proteins
  • Transcription Factors
  • UFD1 protein, human
  • Ubiquitins
  • Ufd1 protein, mouse
  • Zebrafish Proteins
  • hand2 protein, zebrafish