Year: 2009
Type: article
Abstract: Hydrolethalus syndrome (HLS) is a severe fetal malformation syndrome that is inherited by an autosomal recessive manner.HLS belongs to the Finnish disease heritage, an entity of rare diseases that are more prevalent in Finland than in other parts of the world.The phenotypic spectrum of the syndrome is wide and it is characterized by several developmental abnormalities, including hydrocephalus and absent midline structures in the brain, abnormal lobation of the lungs, polydactyly as well as micrognathia and other craniofacial anomalies.Polyhydramnios are relatively frequent during pregnancy.HLS can nowadays be effectively identified by ultrasound scan already at the end of the first trimester of pregnancy.Usually, pregnancy is terminated due to the severe developmental defects of the fetus.One of the main goals in this thesis was to identify and characterize the gene defect underlying HLS.The defect, an A to G point mutation, was found from a previously unknown gene that was named HYLS1.Since HYLS1 was an unknown gene with no relatives in the known gene families, many functional studies were performed in order to unravel the function of the gene and of the protein it codes for.Studies with overexpression cell models showed that the subcellular localization of the HYLS1 protein was different when the wild type and its mutant forms were compared.Wild type protein was mainly localized diffusely in the cytoplasm whereas the mutant form was observed largely in the nucleus in punctate nuclear inclusions.The wild type form was seen to be completely localized in the nucleus when the function of the putative nuclear export signal in HYLS1 was blocked.In addition, HYLS1 was shown to possess transactivation potential which was significantly diminished in the mutant form.When studying possible differences in gene expression in fibroblast cells obtained from HLS cases and healthy controls using the microarray method, several genes belonging to many different cellular pathways (e.g.lipid metabolism, cell cycle regulation, signal transduction) were seen to be differentially expressed.Studies done with neuronal progenitor cells revealed that HLS cells had a higher proliferation rate and a lower apoptosis rate than control cells.Essential novel information was also gathered from studies performed at the tissue level.For example, cholesterol level was shown to be significantly elevated in HLS liver samples.Neuropathological findings of mutation confirmed HLS cases were described for the first time in detail in this study.In addition to neuropathological features described earlier, such as absent midline structures and a keyhole-like opening in the base of the skull, new analyses revealed for example hypothalamic hamartoma as a frequent finding.Microscopically, many developmental defects of the central nervous system were found, these including cortical dysplasia, rosette structures in the cerebral cortex and irregular radial glial cell structures.Also, general pathological findings were described which showed an interestingly wide variation in the HLS phenotype.At the beginning of this thesis work, HYLS1 was an unknown gene with an unknown function.Lots of new information about the function of the gene and the protein was obtained in this study although the precise function of HYLS1 remains to be elucidated.HYLS1 most likely participates in transcriptional regulation and also in the regulation of cholesterol metabolism and the function of HYLS1 is critical for normal fetal development.Identification of the gene defect made it possible to confirm the HLS diagnosis genetically, an aspect that provides valuable information for the families in which a fetus is suspected to have HLS.Studying developmental malformation syndromes such as HLS offers essential new information also for the understanding of molecular and cellular events required for normal fetal development.
Author: Heli Honkala
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1275655750