Abstract
Nonsense variants in KIDINS220/ARMS were identified as the main cause of spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome, a rare disease with birth defects in brachycephaly, neurological disorder, and obesity. The cause of neural cell dysfunction by KIDINS220/ARMS were extensively studied while the cause of obesity in SINO syndrome remains elusive. Here, we identified KIDINS220/ARMS as an adipocyte differentiation-regulating gene. A Chinese family, mother and her two sons, all showed severe symptoms of SINO syndrome. G-banding karyotyping, chromosome microarray analysis, and whole exome sequencing revealed a novel amber mutation, c.3934G>T (p. E1312X), which was close to the C-terminal region of KIDINS220/ARMS and resulted in the premature of the protein. Both the mRNA and protein levels of KIDINS220/ARMS gradually decreased during adipocyte differentiation. Knockdown of KINDINS220/ARMS could prompt adipocyte differentiation and lipid accumulation while overexpression of KIDINS220/ARMS decrease the rate of matured adipocytes. Furthermore, we demonstrated that KIDINS220/ARMS inhibits adipocyte maturation through sustained extracellular signal-regulated kinase signaling. In conclusion, this is the first report about a vertical heredity of severe dominant pathogenic mutation of KIDINS220/ARMS, suggested that KIDINS220/ARMS played a negative role in adipocyte maturation, explained the cause of obesity in SINO syndrome and could highlight the importance of adipocyte differentiation in neuron functions.
Highlights
The syndrome of spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO; MIM# 617296) is an autosomal dominant rare disease with birth defects of cranial and maxillofacial deformity, severe intellectual disability, and obesity, which was first described and linked to heterozygous nonsense kinase D-interacting substrate of 220 kDa (KIDINS220/ankyrin repeat-rich membrane spanning (ARMS)) mutationsKIDINS220/ARMS Regulates Adipocyte Differentiation by Josifova et al (2016) in three unrelated patients
Our results suggested that KIDINS220/ARMS, through sustaining the phosphorylation of extracellular signal-regulated kinase (ERK), could function as a negative regulator for the adipocyte differentiation, the truncated mutation of KIDINS220/ARMS could lead to uncontrolled differentiation and maturation of adipose cells, which caused obesity in SINO patients
To address whether KIDINS220/ARMS had functions in adipocyte differentiation, which was critical to the onset of obesity in childhood (Hausman et al, 2001), we examined the expression level of KINDIS220/ARMS during adipocyte maturation
Summary
KIDINS220/ARMS Regulates Adipocyte Differentiation by Josifova et al (2016) in three unrelated patients. Due to its pivotal roles in development and diverse cellular process, Kidins220/ARMS knockout mice are embryonically lethal at the late stage of gestation with developmental defects in the nervous and cardiovascular system (Cesca et al, 2012). Children carrying the heterozygous mutations of KIDINS220/ARMS showed SINO, which was first identified in three unrelated children and was named “SINO syndrome” by Josifova et al (2016). Six heterozygous causative mutations in KIDINS220/ARMS had been identified as the causes of SINO syndrome in children (Josifova et al, 2016; Yang et al, 2018; Zhao et al, 2019). Patients with SINO syndrome usually had delayed neurological development due to the fundamental functions of KIDINS220/ARMS in the nervous system (Josifova et al, 2016). The potential role of KIDINS220/ARMS in fat metabolism or adipocytes regulation was largely ignored
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