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DGAT1 mutation is linked to a congenital diarrheal disorder
Joel T Haas1, Harland S Winter, Elaine Lim
1Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
Insights
Rare genetic mutations in the DGAT1 gene cause congenital diarrheal disorders (CDDs) in infants. Loss-of-function mutations lead to severe diarrhea, highlighting DGAT1
Area of Science:
- Genetics and Molecular Biology
- Gastroenterology
- Rare Diseases
Background:
- Congenital diarrheal disorders (CDDs) are rare, severe enteropathies presenting early in life.
- Understanding the genetic basis of CDDs is crucial for diagnosis and treatment.
Observation:
- A family of Ashkenazi Jewish descent had two children with severe, intractable diarrhea starting in infancy.
- One child succumbed to complications, while the other showed significant symptom improvement.
- Exome sequencing identified homozygous splice site mutations in the DGAT1 gene in affected children.
Findings:
- The identified DGAT1 mutation resulted in a complete loss of protein function and activity.
- This DGAT1 loss-of-function is identified as a cause of congenital diarrheal disorders.
- Diarrhea is hypothesized to stem from impaired fat absorption and DGAT substrate accumulation.
Implications:
- DGAT1 loss-of-function mutations are a newly identified cause of CDDs.
- This discovery raises concerns regarding therapeutic DGAT1 inhibition in humans.
- Further research is needed to understand DGAT1's role in intestinal function and disease.
Abstract:
Congenital diarrheal disorders (CDDs) are a collection of rare, heterogeneous enteropathies with early onset and often severe outcomes. Here, we report a family of Ashkenazi Jewish descent, with 2 out of 3 children affected by CDD. Both affected children presented 3 days after birth with severe, intractable diarrhea. One child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. Using exome sequencing, we identified a rare splice site mutation in the DGAT1 gene and found that both affected children were homozygous carriers. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. The precise cause of diarrhea is unknown, but we speculate that it relates to abnormal fat absorption and buildup of DGAT substrates in the intestinal mucosa. Our results identify DGAT1 loss-of-function mutations as a rare cause of CDDs. These findings prompt concern for DGAT1 inhibition in humans, which is being assessed for treating metabolic and other diseases.
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