Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis.

Heterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. Through genetic and molecular analyses, we show that Zic1 and Zic4 have Shh-dependent function promoting proliferation of granule cell progenitors. Expression of the Shh-downstream genes Ptch1, Gli1 and Mycn was downregulated in Zic1/4 mutants, although Shh production and Purkinje cell gene expression were normal. Reduction of Shh dose on the Zic1(+/-);Zic4(+/-) background also resulted in cerebellar size reductions and gene expression changes comparable with those observed in Zic1(-/-);Zic4(-/-) mice. Zic1 and Zic4 are additionally required to pattern anterior vermis foliation. Zic mutant folial patterning abnormalities correlated with disrupted cerebellar anlage gene expression and Purkinje cell topography during late embryonic stages; however, this phenotype was Shh independent. In Zic1(+/-);Zic4(+/-);Shh(+/-), we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.

Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation.

Dandy-Walker malformation (DWM; OMIM #220200) is a common but poorly understood congenital cerebellar malformation in humans. Through physical mapping of 3q2 interstitial deletions in several individuals with DWM, we defined the first critical region associated with DWM, encompassing two adjacent Zinc finger in cerebellum genes, ZIC1 and ZIC4. Mice with a heterozygous deletion of these two linked genes have a phenotype that closely resembles DWM, providing a mouse model for this malformation.

Molecular and neuroimaging findings in pontocerebellar hypoplasia type 2 (PCH2): is prenatal diagnosis possible?

The pontocerebellar hypoplasias (PCH) are a group of early-onset, autosomal recessive disorders resulting in abnormal growth and function of the brainstem and cerebellum. PCH type 2 (PCH2) is characterized by respiratory and feeding difficulties at birth, extrapyramidal dyskinesia, severe developmental impairment, progressive microcephaly and frequent death in childhood. Neuropathologic findings include diffuse cerebral gliosis with white matter changes, hypoplastic pons with depletion of neurons in the pontine nuclei, hypoplastic cerebellar hemispheres due to short cerebellar folia with poor branching, segmental loss of dentate, inferior olivary, and ventral pontine nuclei, and near absence of transverse pontine fibers with preservation of long fiber tracts and spinal anterior horn cells. On brain imaging, the cerebellar hemispheres appear very flat, and are more severely involved than the vermis. Most patients with PCH2 have mutations in TSEN54, with occasional mutations found in TSEN34 or TSEN2, genes that encode subunits of tRNA splicing endonuclease. Although this is a congenital disorder of pontocerebellar dysgenesis with fetal onset of neurodegeneration and symptoms at birth, prenatal imaging is unreliable in diagnosing this disorder in utero. We report on IVF dizygous twins with detailed prenatal imaging that failed to reveal any cerebellar abnormalities. Direct sequence analysis of TSEN54 showed homozygosity for c.919G>T, the common founder mutation in most PCH2 patients, and both parents were heterozygous for this mutation. We found no evidence of cerebellar dysgenesis on prenatal ultrasounds, but MRI tractography showed absence of pontine crossing fibers, a unique feature that might be useful for prenatal diagnosis of this condition.

Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32.

We have identified a female patient with a complex phenotype that includes complete agenesis of the corpus callosum, bilateral periventricular nodular heterotopia, and bilateral chorioretinal and iris colobomas. Karyotype analysis revealed an apparently balanced, reciprocal, de novo chromosome translocation t(2;9)(p24;q32). Physical mapping of the translocation breakpoint by fluorescence in situ hybridization and PCR analysis led to the identification of two novel, ubiquitously expressed, Zn-finger-encoding transcripts that are disrupted in this patient. Unexpectedly, the rearrangement produced in-frame reciprocal fusion transcripts, making genotype-phenotype correlation difficult.