Increased LIS1 expression affects human and mouse brain development.

Area of Science:

• Genetics
• Developmental Biology
• Neuroscience

Background:

• Deletions in 17p13.3 involving PAFAH1B1 (LIS1) cause isolated lissencephaly sequence.
• Extended deletions including YWHAE cause Miller-Dieker syndrome.

Purpose of the Study:

• To characterize the clinical consequences of submicroscopic duplications in 17p13.3 involving PAFAH1B1 and/or YWHAE.
• To investigate the effects of increased LIS1 dosage on brain development using a reverse genomics approach.

Main Methods:

• Identified seven unrelated individuals with submicroscopic 17p13.3 duplications.
• Utilized a reverse genomics approach to correlate genetic findings with clinical outcomes.
• Generated transgenic mice with conditional LIS1 overexpression in the developing brain.

Main Results:

• Increased PAFAH1B1 dosage is associated with mild brain abnormalities, developmental delay, and failure to thrive.
• YWHAE duplication increases macrosomia risk, mild developmental delay, pervasive developmental disorder, and shared facial dysmorphies.
• LIS1 overexpression in mice resulted in decreased brain size, increased apoptosis, and distorted cellular organization.

Conclusions:

• Increased LIS1 expression in the developing brain leads to brain abnormalities in both mice and humans.
• Duplications in 17p13.3 involving PAFAH1B1 and YWHAE have distinct and overlapping clinical consequences.
• This study highlights the critical role of precise gene dosage in normal brain development.