Minimal evidence for a direct involvement of twisted gastrulation homolog 1 ( TWSG1) gene in human holoprosencephaly

• Published in: Molecular genetics and metabolism Vol. 102; no. 4; pp. 470 - 480
• Main Authors: Kauvar, Emily F., Hu, Ping, Pineda-Alvarez, Daniel E., Solomon, Benjamin D., Dutra, Amalia, Pak, Evgenia, Blessing, Brooke, Proud, Virginia, Shanske, Alan L., Stevens, Cathy A., Rosenfeld, Jill A., Shaffer, Lisa G., Roessler, Erich, Muenke, Maximilian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2011
• Subjects: 18p; Abnormalities, Multiple - genetics; Adult; Animals; Base Sequence; BMP; Bone morphogenetic proteins; Bone Morphogenetic Proteins - metabolism; Case-Control Studies; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 18; Comparative Genomic Hybridization; craniofacial growth; Environmental factors; Etiology; Female; Forebrain; Gastrulation; Gene deletion; Gene mapping; Genetic Association Studies; Hedgehog protein; Holoprosencephaly; Holoprosencephaly - epidemiology; Holoprosencephaly - genetics; HPE; Humans; In Situ Hybridization, Fluorescence; Nucleic Acid Denaturation; Sequence Analysis, DNA; Signal transduction; Signal Transduction - genetics; Tsg; Twisted gastrulation homolog 1; TWSG1; TWSG1; BMP; Tsg; 18p; Twisted gastrulation homolog 1; HPE; Holoprosencephaly
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2010.12.008

Holoprosencephaly (HPE) is the most common disorder of human forebrain and facial development. Presently understood etiologies include both genetic and environmental factors, acting either alone, or more likely, in combination. The majority of patients without overt chromosomal abnormalities or recognizable associated syndromes have unidentified etiologies. A potential candidate gene,
Twisted Gastrulation Homolog 1 (
TWSG1), was previously suggested as a contributor to the complex genetics of human HPE based on (1) cytogenetic studies of patients with 18p deletions, (2) animal studies of
TWSG1 deficient mice, and (3) the relationship of TWSG1 to bone morphogenetic protein (BMP) signaling, which modulates the primary pathway implicated in HPE, Sonic Hedgehog (SHH) signaling. Here we present the first analysis of a large cohort of patients with HPE for coding sequence variations in
TWSG1. We also performed fine mapping of 18p for a subset of patients with partial 18p deletions. Surprisingly, minimal evidence for alterations of
TWSG1 was found, suggesting that sequence alterations of
TWSG1 are neither a common direct cause nor a frequent modifying factor for human HPE pathologies.