Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients ...Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.展开更多
Sterol regulatory element-binding factor-1 and-2(SREBF1 and SREBF2)are important transcription factors involved in the regulating lipid homeostasis.Based on the essential role of SREBF1 and SREBF2,we measured the mRNA...Sterol regulatory element-binding factor-1 and-2(SREBF1 and SREBF2)are important transcription factors involved in the regulating lipid homeostasis.Based on the essential role of SREBF1 and SREBF2,we measured the mRNA expression levels of the two genes in six various tissues at different growth points.Our results showed that the SREBF1 and SREBF2 were expressed in all six tissues examined in Erlang mountainous chicken(SD02)at 42 d,and were expressed abundantly in the uropygial gland and liver,with relatively lowest levels of expression in the abdominal fat,sebum cutaneum and leg muscle.The expression ratio of SREBF1 and SREBF2 in breast muscle,leg muscle,sebum cutaneum and uropygial gland exhibited a"decline-rise"trend.However,in liver,the expression ratio of these two genes exhibited a"decline-rise-decline"trend.Meanwhile,the expression level of SREBF1 gene of all tissues was lower than that of SREBF2 except for uropygial gland.The findings will provide important references for further function investigation of the two genes involved in fat deposition in chickens.展开更多
基金supported by the grants from the National Natural Science Foundation of China to Zhi-Ying Wu(82230062,Beijing),Qiao Wei(82402156,Beijing),and Wanzhong Ge(31970668,Beijing)the research foundation for distinguished scholar of Zhejiang University(188020-193810101/089,Hangzhou)to Zhi-Ying Wu
文摘Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.
基金Key Technology Support Program of Sichuan Province(2018NZDZX0004,2016NZ0104)Financial Project of Sichuan Province(SASA2020CZYX002)。
文摘Sterol regulatory element-binding factor-1 and-2(SREBF1 and SREBF2)are important transcription factors involved in the regulating lipid homeostasis.Based on the essential role of SREBF1 and SREBF2,we measured the mRNA expression levels of the two genes in six various tissues at different growth points.Our results showed that the SREBF1 and SREBF2 were expressed in all six tissues examined in Erlang mountainous chicken(SD02)at 42 d,and were expressed abundantly in the uropygial gland and liver,with relatively lowest levels of expression in the abdominal fat,sebum cutaneum and leg muscle.The expression ratio of SREBF1 and SREBF2 in breast muscle,leg muscle,sebum cutaneum and uropygial gland exhibited a"decline-rise"trend.However,in liver,the expression ratio of these two genes exhibited a"decline-rise-decline"trend.Meanwhile,the expression level of SREBF1 gene of all tissues was lower than that of SREBF2 except for uropygial gland.The findings will provide important references for further function investigation of the two genes involved in fat deposition in chickens.
