Truncating mutations in APP cause a distinct neurological phenotype
Steven Klein1, Alexander Goldman1, Hane Lee2
1Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
Abstract:
Dominant missense mutations in the amyloid β (Aβ) precursor protein (APP) gene have been implicated in early onset Alzheimer disease. These mutations alter protein structure to favor the pathologic production of Aβ. We report that homozygous nonsense mutations in APP are associated with decreased somatic growth, microcephaly, hypotonia, developmental delay, thinning of the corpus callosum, and seizures. We compare the phenotype of this case to those reported in mouse models and demonstrate multiple similarities, strengthening the role of amyloid precursor protein in normal brain function and development. Ann Neurol 2016;80:456-460.
Insights
Homozygous nonsense mutations in the amyloid precursor protein (APP) gene cause severe developmental issues, distinct from Alzheimer disease. This highlights APP's crucial role in normal brain development.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Dominant missense mutations in the amyloid precursor protein (APP) gene are linked to early-onset Alzheimer disease.
- These mutations promote the pathological production of amyloid beta (Aβ) by altering APP structure.
Observation:
- Homozygous nonsense mutations in the APP gene present a distinct clinical phenotype.
- Observed symptoms include decreased somatic growth, microcephaly, hypotonia, developmental delay, corpus callosum thinning, and seizures.
Findings:
- The study details a case of homozygous nonsense mutations in APP.
- The observed phenotype shares similarities with established mouse models of APP dysfunction.
Implications:
- This research underscores the critical role of amyloid precursor protein (APP) in normal human brain development and function.
- Understanding APP's diverse roles is crucial for both neurodevelopmental disorders and Alzheimer disease research.
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