Unraveling the disease pathogenesis behind lethal hydrolethalus syndrome revealed multiple changes in molecular and cellular level

Heli Honkala,Kirmo Wartiovaara,Niklas Pakkasjärvi,Marjo Kestilä,Matti Jauhiainen,Jenni Lahtela,Massimiliano Gentile,Riitta Salonen,Heli Fox

doi:10.1186/1755-8417-2-2

Heli Honkala, Kirmo Wartiovaara + Show 7 more

Open Access

https://doi.org/10.1186/1755-8417-2-2

Copy DOI

Abstract

BackgroundHydrolethalus 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.ResultsTo 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.ConclusionIn 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.

Highlights

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
Disease pathogenesis of hydrolethalus syndrome (HLS) Microarray analysis Owing the dramatic phenotype of HLS fetuses and the lack of exact information on HYLS1 function, we performed genome-wide gene expression analysis of fetal skin fibroblast cell lines (HLS N = 3, control N = 4) to obtain novel data on cellular pathways influencing the HLS pathogenesis
We obtained a total of 802 transcripts to evaluate by analysis of variance (ANOVA; t-test) statistical testing and as a result, we chose a statistically significant subgroup of these to be analyzed further

Summary

Introduction

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. Immature cerebral cortex, abnormalities in radial glial cells and hypothalamic hamartoma are among key findings in the CNS of HLS fetuses. HLS is characterized by a severe central nervous system (CNS) malformation with hydrocephaly and absent midline structures of the brain. The main neuropathological findings include a unique open-book appearance of the brain midline, the 'key-hole' defect in the base of the scull, a massive accumulation of cerebrospinal fluid, a dysplastic cortex, agenesis of the hippocampi, hypoplastic cerebellum and brain stem as well as hypothalamic hamartoma. HLS is enriched in the Finnish population with an incidence of at least 1:20,000 [3]

Methods

Results

Discussion

Conclusion