Abstract
Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) is a cytoplasmic tyrosine phosphatase that is highly expressed in hematopoietic cells and in the CNS and exerts opposite effects on signal transduction by exerting a neuroprotective or proapoptotic effect. Several mutations of SHP-2 have been found in children with myeloproliferative disorders or malignant leukemia, and some of these can affect brain development. In the present study, we aimed to identify and functionally characterize genetic variations in SHP-2 in 72 preterm and 58 full-term infants and to evaluate the effect of the variations on neurodevelopment in preterm infants. Twelve genetic variations were identified. Among them, two variations in the SHP-2 promoter, g.-317C > T and g.-273G > A, were found to significantly increase promoter activity, and the frequency of g.-273G > A was higher in preterm infants than in full-term infants. Two transcription factors, NF-κB and GABPα, were found to be involved in the transcriptional regulation of SHP-2 by the two above-mentioned variations. In particular, we found that g.-273G > A was significantly associated with delayed myelination and poor motor development in preterm infants. Our results suggest that a functional promoter variation in SHP-2 is associated with spontaneous preterm birth itself as well as white matter myelination and neurodevelopment.
Highlights
Preterm birth is defined as live birth before 37 gestational weeks[1]
We reckoned that SHP-2 variations might be associated with neurodevelopment in preterm infants, because SHP-2 is highly expressed in the central nervous system (CNS) and works as a regulator of Ras-Erk signaling involved in neurodevelopment
SHP-2 is ubiquitously expressed in mammalian tissues with high levels of expression in hematopoietic cells and in the CNS and has been shown to be essential for organ development and hematopoiesis[26]
Summary
Preterm birth is defined as live birth before 37 gestational weeks[1]. the mortality rates related to preterm birth have decreased in recent years, neurological impairments in preterm infants remain a problem[2]. Preterm birth is caused due to multiple factors including inflammation, infection, reactive oxygen species (ROS), and genetic factors[3, 4] These factors affect immature neuronal cells and result in poor neurological outcome later[5]. Noonan syndrome, which is a frequent genetic disease with an estimated prevalence of approximately 1/2,000 living births, is caused by genetic variations in genes involved in Ras-Erk signaling, including SHP-224. A nonsynonymous GOF variation in SHP-2, D61G, is associated with aspects of neurodevelopment such as spatial learning and memory deficits in Noonan syndrome[25] These results support a disease-associated function for SHP-2 against leukemia and brain development. We hypothesized that genetic variations in SHP-2 affect spontaneous preterm birth by regulating cytokines and a signaling pathway under ROS-induced oxidative stress. To evaluate the effect of the genetic variations in SHP-2 on neurodevelopment in preterm infants, we further analyzed the degree of myelination according to the functional genetic variation in SHP-2 using tract-based spatial statistics (TBSS) and assessed neurodevelopment using the Bayley Scale of Infant and Toddler Development, third edition (Bayley-III), in preterm infants at 18–22 months of corrected age
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