title: Unraveling the disease pathogenesis behind lethal hydrolethalus syndrome revealed multiple changes in molecular and cellular level.
abstract: BACKGROUND
  Hydrolethalus syndrome (HLS) is a severe fetal malformation syndrome characterized by multiple developmental anomalies, including central nervous system (CNS) malformation such as hydrocephaly and absent midline structures of the brain, micrognathia, defective lobation of the lungs and polydactyly. Microscopically, immature cerebral cortex, abnormalities in radial glial cells and hypothalamic hamartoma are among key findings in the CNS of HLS fetuses. HLS is caused by a substitution of aspartic acid by glycine in the HYLS1 protein, whose function was previously unknown.
  
  
  RESULTS
  To provide insight into the disease mechanism(s) of this lethal disorder we have studied different aspects of HLS and HYLS1. A genome-wide gene expression analysis indicated several upregulated genes in cell cycle regulatory cascades and in specific signal transduction pathways while many downregulated genes were associated with lipid metabolism. These changes were supported by findings in functional cell biology studies, which revealed an increased cell cycle rate and a decreased amount of apoptosis in HLS neuronal progenitor cells. Also, changes in lipid metabolism gene expression were reflected by a significant increase in the cholesterol levels of HLS liver tissues. In addition, based on our functional studies of HYLS1, we propose that HYLS1 is a transcriptional regulator that shuffles between the cytoplasm and the nucleus, and that when HYLS1 is mutated its function is significantly altered.
  
  
  CONCLUSIONS
  In this study, we have shown that the HYLS1 mutation has significant consequences in the cellular and tissue levels in HLS fetuses. Based on these results, it can be suggested that HYLS1 is part of the cellular transcriptional regulatory machinery and that the genetic defect has a widespread effect during embryonic and fetal development. These findings add a significant amount of new information to the pathogenesis of HLS and strongly suggest an essential role for HYLS1 in normal fetal development.
authors.affiliation: National Institute for Health and Welfare and FIMM, Institute for Molecular Medicine Finland, Helsinki, Finland. marjo.kestila@thl.fi.
authors.forename: Heli
authors.initials: H
authors.lastname: Honkala
authors.forename: Jenni
authors.initials: J
authors.lastname: Lahtela
authors.forename: Heli
authors.initials: H
authors.lastname: Fox
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gentile
authors.forename: Niklas
authors.initials: N
authors.lastname: Pakkasjärvi
authors.forename: Riitta
authors.initials: R
authors.lastname: Salonen
authors.forename: Kirmo
authors.initials: K
authors.lastname: Wartiovaara
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Marjo
authors.initials: M
authors.lastname: Kestilä