title: Complex brain malformations associated with chromosome 6q27 gain that includes THBS2, which encodes thrombospondin 2, an astrocyte-derived protein of the extracellular matrix.
abstract: This case describes the autopsy findings of a 2-month-old male infant with extensive and severe developmental brain abnormalities, including microcephaly, neocortical neuronal layering abnormalities, leptomeningeal heterotopias, commissural agenesis, and cerebellar and brainstem hypoplasia. Microarray analysis identified a gain in chromosome band 6q27, which includes the entire coding region of THBS2. THSB2 encodes thrombospondin 2 (TSP2), an astrocyte secreted protein of the extracellular matrix that promotes synaptogenesis, neurite outgrowth, and cerebellar granule cell migration. Thrombospondin 2 is not a matrix structural protein; instead it serves as an extracellular modulator of cell function, so it is considered a matricellular protein. The neuropathological findings at autopsy are compatible with perturbations in several known functions of TSP2 and demonstrate that TSP2 dysregulation can have a significant negative impact on human brain development. Furthermore, this case demonstrates the important role of astrocytes in human brain development.
authors.affiliation: 1 The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: Melissa N
authors.initials: MN
authors.lastname: Burnside
authors.forename: Robert E
authors.initials: RE
authors.lastname: Pyatt
authors.forename: Anna
authors.initials: A
authors.lastname: Hughes
authors.forename: Peter B
authors.initials: PB
authors.lastname: Baker
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
mesh_terms: D001253:Astrocytes / Q000166:cytology*; D001344:Autopsy; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000002:abnormalities* / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement; D058674:Chromosome Duplication; D002896:Chromosomes, Human, Pair 6 / Q000648:ultrastructure*; D055028:Comparative Genomic Hybridization; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009474:Neurons / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019699:Thrombospondins / Q000235:genetics*; D055815:Young Adult; D000099262:Thrombospondin 2
chemical_list: D019699:Thrombospondins; D000099262:Thrombospondin 2
keywords: THBS2; axon elongation; brain malformation; microcephaly; neuronal migration; sudden unexpected death in infancy; thrombospondin 2