bims-glecem 2022-11-20 papers

Issue of 2022‒11‒20
four papers selected by
Dipsikha Biswas, Københavns Universitet

Yi Chuan. 2022 Nov 20. 44(11): 1063-1071

Diagnosis and genetic analysis of a case with glycogen storage disease type V caused by compound heterozygous mutations in the PYGM gene.

Wan-Zi Jiang, Yi-Wen Xu, Yi-Wen Wang, Xiao-Cheng Zhu, Ying-Yun Gong, Hong-Wen Zhou, Zhen-Zhen Fu.

Glycogen storage disease type V is an autosomal recessive genetic disorder caused by muscle glycogen phosphorylase (PYGM) deficiency, which is characterized by exercise intolerance, second wind phenomena and high level of serum creatine kinase. In this study, we reported a Chinese young man with glycogen storage disease type V, with lower extremity weakness after exercise, increased creatine kinase, and slight fat infiltration in the posterior group of thigh muscle by magnetic resonance imaging (MRI). The proband had complex heterozygous PYGM disease-causing mutations, including c.308T>C (p.L103P) variant transmitted from the mother and c.260_261delCT (p.S87Ffs*23) from the father, of which the former was a novel PYGM mutation. This study enriched the PYGM pathogenic gene mutation spectrum, contributed to improve clinicians' understanding of glycogen storage disease type V and provided a reference for further genetic study of the disease.

Keywords: McArdle disease; PYGM; glycogen storage disease type V; rare disease

DOI: https://doi.org/10.16288/j.yczz.22-223

Nat Commun. 2022 Nov 17. 13(1): 7038

N6-methyladenosine modification governs liver glycogenesis by stabilizing the glycogen synthase 2 mRNA.

Xiang Zhang, Huilong Yin, Xiaofang Zhang, Xunliang Jiang, Yongkang Liu, Haolin Zhang, Yingran Peng, Da Li, Yanping Yu, Jinbao Zhang, Shuli Cheng, Angang Yang, Rui Zhang.

Hepatic glycogen is the main source of blood glucose and controls the intervals between meals in mammals. Hepatic glycogen storage in mammalian pups is insufficient compared to their adult counterparts; however, the detailed molecular mechanism is poorly understood. Here, we show that, similar to glycogen storage pattern, N6-methyladenosine (m6A) modification in mRNAs gradually increases during the growth of mice in liver. Strikingly, in the hepatocyte-specific Mettl3 knockout mice, loss of m6A modification disrupts liver glycogen storage. On the mechanism, mRNA of Gys2, the liver-specific glycogen synthase, is a substrate of METTL3 and plays a critical role in m6A-mediated glycogenesis. Furthermore, IGF2BP2, a "reader" protein of m6A, stabilizes the mRNA of Gys2. More importantly, reconstitution of GYS2 almost rescues liver glycogenesis in Mettl3-cKO mice. Collectively, a METTL3-IGF2BP2-GYS2 axis, in which METTL3 and IGF2BP2 regulate glycogenesis as "writer" and "reader" proteins respectively, is essential on maintenance of liver glycogenesis in mammals.

DOI: https://doi.org/10.1038/s41467-022-34808-2

Genet Med. 2022 Nov 17. pii: S1098-3600(22)00974-1. [Epub ahead of print]

Evaluating brain white matter hyperintensity, IQ scores, and plasma neurofilament light chain concentration in early-treated patients with infantile-onset Pompe disease.

Yu-Kang Hsu, Yin-Hsiu Chien, Steven Shinn-Forng Peng, Wuh-Liang Hwu, Wang-Tso Lee, Ni-Chung Lee, Eric Po-Yu Huang, Wen-Chin Weng.

PURPOSE: The study aimed to describe central nervous system (CNS) progression in patients with infantile-onset Pompe disease (IOPD) and explore the potential clinical impact and predictors.METHODS: Patients with IOPD treated with enzyme replacement therapy were longitudinally followed with brain magnetic resonance imaging (MRI) and evaluation for IQ scores from 2004 to 2021. Investigation of CNS involvement focused on white matter (WM) abnormalities and was quantified using a scoring system for metachromatic leukodystrophy. MRI scores were correlated with plasma neurofilament light chain (NfL) concentration and IQ scores.
RESULTS: A total of 19 patients who started enzyme replacement therapy at a mean age of 26 days were analyzed; the median age at last examination was 12.1 (range = 1.7-19) years. MRI abnormalities were found in all patients, from supratentorial central WM to U-fibers, then to infratentorial WM, and eventually to gray matter. MRI scores progressed (n = 16) at variable rates (range = 0.8-2.7/y) and were positively correlated with age (n = 16) and negatively correlated with IQ scores (n = 8). Plasma NfL concentration was positively correlated with MRI scores (r2 = 0.8569; P < .001; n = 13).
CONCLUSION: Our results suggest that the progression of CNS involvement in IOPD may be associated with neuroaxonal injury and decreased IQ scores. NfL could serve as a biomarker for CNS involvement in IOPD.

Keywords: Brain MRI; IQ score; Infantile-onset Pompe disease; Neuroaxonal injury; Neurofilament light chain

DOI: https://doi.org/10.1016/j.gim.2022.10.005

Lipids Health Dis. 2022 Nov 16. 21(1): 121

WY-14643 attenuates lipid deposition via activation of the PPARα/CPT1A axis by targeting Gly335 to inhibit cell proliferation and migration in ccRCC.

Rui Wang, Jun Zhao, Jiacheng Jin, Yun Tian, Lan Lan, Xuejian Wang, Liang Zhu, Jianbo Wang.

BACKGROUND: Histologically, cytoplasmic deposits of lipids and glycogen are common in clear cell renal cell carcinoma (ccRCC). Owing to the significance of lipid deposition in ccRCC, numerous trials targeting lipid metabolism have shown certain therapeutic potential. The agonism of peroxisome proliferator-activated receptor-α (PPARα) via ligands, including WY-14,643, has been considered a promising intervention for cancers.METHODS: First, the effects of WY-14,643 on malignant behaviors were investigated in ccRCC in vitro. After RNA sequencing, the changes in lipid metabolism, especially neutral lipids and glycerol, were further evaluated. Finally, the underlying mechanisms were revealed.
RESULTS: Phenotypically, the proliferation and migration of ccRCC cells treated with WY-14,643 were significantly inhibited in vitro. A theoretical functional mechanism was proposed in ccRCC: WY-14,643 mediates lipid consumption by recognizing carnitine palmitoyltransferase 1 A (CPT1A). Activation of PPARα using WY-14,643 reduces lipid deposition by increasing the CPT1A level, which also suppresses the NF-κB signaling pathway. Spatially, WY-14,643 binds and activates PPARα by targeting Gly335.
CONCLUSION: Overall, WY-14,643 suppresses the biological behaviors of ccRCC in terms of cell proliferation, migration, and cell cycle arrest. Furthermore, its anticancer properties are mediated by the inhibition of lipid accumulation, at least in part, through the PPARα/CPT1A axis by targeting Gly335, as part of the process, NF-κB signaling is also suppressed. Pharmacological activation of PPARα might offer a new treatment option for ccRCC.

Keywords: CPT1A; Lipid accumulation; PPARα; WY-14643; ccRCC

DOI: https://doi.org/10.1186/s12944-022-01726-7