Abstract
Objective: To identify the underlying molecular basis of a familial developmental disorder characterized by chorea, marked speech delay, and learning difficulties in 4 sisters from a consanguineous family.
Methods: Whole-exome analysis of DNA of the 2 older patients followed by Sanger sequencing of the mutated exon in all family members.
Results: A homozygous deleterious mutation, p.C291X, was identified in the GPR88 gene in both exome analyses. The mutation segregated with the disease in the family and was absent from a large cohort of controls.
Conclusions: Homozygous deleterious mutation in GPR88 in humans is associated with marked speech delay, learning disabilities, and chorea, which manifest at 8–9 years of age. The finding is consistent with the reported abundant expression of GPR88 in the striatum and the hyperkinetic activity and learning impairment observed in GPR88 knockout mice. Although further functional characterization is needed, the finding underscores the importance of GPR88 in movement control and learning.
GLOSSARY
- ExAC=
- Exome Aggregation Consortium;
- GPext=
- globus pallidus pars externa;
- GPint=
- globus pallidus pars interna;
- MAF=
- minor allele frequency;
- MSN=
- medium spiny neuron
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was waived at the discretion of the Editors.
Supplemental data at Neurology.org/ng
- Received October 21, 2015.
- Accepted in final form January 15, 2016.
- © 2016 American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
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