{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:08:54Z","timestamp":1768972134821,"version":"3.49.0"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,6,18]],"date-time":"2013-06-18T00:00:00Z","timestamp":1371513600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2014,5]]},"abstract":"<jats:p>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\u201318\u2009weeks gestation in three full sisters born to healthy, non\u2010consanguineous parents. Analysis of index cases and parents included familial exome sequencing, karyotyping, and genome\u2010wide single nucleotide polymorphism (<jats:styled-content style=\"fixed-case\">SNP<\/jats:styled-content>) array. From proband, control and unrelated microcephalic fetal cortical tissue, we compared gene expression of <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> and targeted immunohistochemistry. Each daughter was homozygous for a rare, non\u2010synonymous, deleterious variant in the <jats:italic><jats:styled-content style=\"fixed-case\">MKL2<\/jats:styled-content><\/jats:italic> gene and heterozygous for a private 185\u2009kb deletion on the paternal allele, upstream and in cis with his <jats:italic><jats:styled-content style=\"fixed-case\">MKL2<\/jats:styled-content><\/jats:italic> variant allele, eliminating 24 <jats:styled-content style=\"fixed-case\">CArG<\/jats:styled-content> transcription factor binding sites and <jats:styled-content style=\"fixed-case\">MIR4718<\/jats:styled-content>. <jats:italic><jats:styled-content style=\"fixed-case\">MKL1<\/jats:styled-content><\/jats:italic> was underexpressed in probands. Dysfunction of <jats:italic><jats:styled-content style=\"fixed-case\">MKL2<\/jats:styled-content><\/jats:italic> and its transcriptional coactivation partner, serum response factor (<jats:styled-content style=\"fixed-case\">SRF<\/jats:styled-content>), was supported by a decrease in gene and protein expression of <jats:styled-content style=\"fixed-case\">PCTAIRE1<\/jats:styled-content>, a downstream target of <jats:styled-content style=\"fixed-case\">MKL2<\/jats:styled-content>:<jats:styled-content style=\"fixed-case\">SRF<\/jats:styled-content> heterodimer transcriptional activation, previously shown to result in severe microcephaly in murine models. While disruption of the <jats:styled-content style=\"fixed-case\">MKL2<\/jats:styled-content>:<jats:styled-content style=\"fixed-case\">SRF<\/jats:styled-content> 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.<\/jats:p>","DOI":"10.1111\/cge.12197","type":"journal-article","created":{"date-parts":[[2013,5,21]],"date-time":"2013-05-21T18:11:36Z","timestamp":1369159896000},"page":"423-432","source":"Crossref","is-referenced-by-count":13,"title":["Genetic variation in <i><scp>MKL2<\/scp><\/i> and decreased downstream <scp>PCTAIRE1<\/scp> expression in extreme, fatal primary human microcephaly"],"prefix":"10.1111","volume":"85","author":[{"given":"E.I.","family":"Ramos","sequence":"first","affiliation":[{"name":"Center for Genome Sciences and Systems Biology Washington University School of Medicine St. Louis MO 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