Abstract
The genetic mechanisms driving normal brain development remain largely unknown. We performed genomic and immunohistochemical characterization of a novel, fatal human phenotype including extreme microcephaly with cerebral growth arrest at 14–18 weeks gestation in three full sisters born to healthy, non-consanguineous parents. Analysis of index cases and parents included familial exome sequencing, karyotyping, and genome-wide single nucleotide polymorphism (SNP) array. From proband, control and unrelated microcephalic fetal cortical tissue, we compared gene expression of RNA and targeted immunohistochemistry. Each daughter was homozygous for a rare, non-synonymous, deleterious variant in the MKL2 gene and heterozygous for a private 185 kb deletion on the paternal allele, upstream and in cis with his MKL2 variant allele, eliminating 24 CArG transcription factor binding sites and MIR4718. MKL1 was underexpressed in probands. Dysfunction of MKL2 and its transcriptional coactivation partner, serum response factor (SRF), was supported by a decrease in gene and protein expression of PCTAIRE1, a downstream target of MKL2:SRF heterodimer transcriptional activation, previously shown to result in severe microcephaly in murine models. While disruption of the MKL2:SRF axis has been associated with severe microcephaly and disordered brain development in multiple model systems, the role of this transcription factor complex has not been previously demonstrated in human brain development.
Highlights
We present an extreme human phenotype that includes developmental anomalies of the heart and lungs and lethal microcephaly with apparent brain growth arrest between 14 and 18 weeks
We suggest that disruption of the Megakaryoblastic Leukemia 2 (MKL2):serum response factor (SRF) gene transcription pathway, perhaps through diminished MKL2 heterodimerization with SRF due to the point mutation in the basic domain followed by the lack of critical CArG binding domains removed by the private deletion, accounts for extreme microcephaly in the affected infants and support this conclusion with the observation of reduced PCTAIRE1 gene and protein expression
A lack of proper protein function is supported by decreased anti-PCTAIRE1 staining, similar to functional studies in animal models resulting in severe microcephaly [4]
Summary
MKL2 has previously been associated with brain and cardiac abnormalities due to disruption of the MKL2:SRF transcription factor axis [2,3,4,5,6]. Conditional brain-specific knockout of Mkl in a Mkl1 −/− murine background phenocopied the neurological abnormalities seen in Srf -null mice and led to lethality between postnatal days 16–21 [4]. Despite these results, no developmental anomalies secondary to perturbations in this pathway have been described in humans
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