Brockschmidt, A., Todt, U., Ryu, S., Hoischen, A., Landwehr, C., Birnbaum, S., Frenck, W., Radlwimmer, B., Lichter, P., Engels, H., Driever, W., Kubisch, C.,and Weber, R.G. (2007) Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum. Mol. Genet.. 16(12):1488-1494.
Pitt-Hopkins syndrome (PHS) is a rare mental retardation syndrome mainly characterized by severe motor and mental retardation (MR) including absent language development, a characteristic facial gestalt, and episodes of hyperventilation. We report on a female patient with PHS showing severe MR with absent speech, pronounced muscular hypotonia, ataxia, distinctive facial features such as a coarse face, a broad nasal bridge, and a wide mouth, and hyperventilation attacks. In this patient, genomic profiling by array-based comparative genomic hybridization and FISH studies detected and confirmed a de novo 0.5 Mb deletion in 18q21.2 containing a single gene, the basic helix-loop-helix transcription factor TCF4. cDNA and genomic analyses in the patient and her parents demonstrated TCF4 haploinsufficiency as the underlying cause of the disease. Analysis of the embryonal expression pattern of the Danio rerio ortholog, tcf4, by whole mount in situ hybridization showed a highly specific expression domain in the pallium of the telencephalon during late somitogenesis, when the patterning of the zebrafish brain is advanced and neural differentiation commences. Later expression domains were restricted to several regions in the CNS, including continued expression in the pallium of the telencephalon, and starting expression in the diencephalon (thalamus, ventral thalamus and posterior tuberculum), the midbrain tegmentum, the hindbrain, and the branchial arches. This expression pattern correlates with the clinical phenotype. Our results show that haploinsufficiency of TCF4 causes PHS, and suggest that Danio rerio is a valuable model to study the molecular pathogenesis of PHS and the role of TCF4 in brain development.