bims-meglyc 2024-02-11 papers

Issue of 2024–02–11
five papers selected by
Silvia Radenkovic

Stem Cell Res. 2023 Dec;pii: S1873-5061(23)00221-0. [Epub ahead of print]73 103235

Generation of human induced pluripotent stem cell line (AOUMEYi001-A) from a patient affected by Congenital disorders of glycosylation (ALG8-CDG) using self-replicating RNA vector.

Rodolfo Tonin, Federica Feo, Silvia Falliano, Lorenzo Ferri, Laura Giunti, Martino Calamai, Elena Procopio, Francesco Mari, Valerio Conti, Ilaria Fanelli, Franco Bambi, Renzo Guerrini, Amelia Morrone.

Congenital Disorders of Glycosylation (CDG) are rare inherited metabolic diseases caused by genetic defects in the glycosylation of proteins and lipids. In this study, we describe the generation and characterization of one human induced pluripotent stem cell (hiPSC) line from a 15-year-old male patient with CDG. The patient carried three variants, one (c.122G > A; p.Arg41Gln) inherited from his father and two (c.445 T > G; p.Leu149Arg and the novel c.980C > G; p.Thr327Arg) inherited from his mother in the ALG8 gene (OMIM #608103). The generated hiPSC line shows a normal karyotype, expresses pluripotency markers, and is able to differentiate into the three germ layers.

DOI: https://doi.org/10.1016/j.scr.2023.103235

Cells. 2024 Feb 05. pii: 289. [Epub ahead of print]13(3):

Brain-Type Glycogen Phosphorylase (PYGB) in the Pathologies of Diseases: A Systematic Review.

Caiting Yang, Haojun Wang, Miaomiao Shao, Fengyu Chu, Yuyu He, Xiaoli Chen, Jiahui Fan, Jingwen Chen, Qianqian Cai, Changxin Wu.

Glycogen metabolism is a form of crucial metabolic reprogramming in cells. PYGB, the brain-type glycogen phosphorylase (GP), serves as the rate-limiting enzyme of glycogen catabolism. Evidence is mounting for the association of PYGB with diverse human diseases. This review covers the advancements in PYGB research across a range of diseases, including cancer, cardiovascular diseases, metabolic diseases, nervous system diseases, and other diseases, providing a succinct overview of how PYGB functions as a critical factor in both physiological and pathological processes. We present the latest progress in PYGB in the diagnosis and treatment of various diseases and discuss the current limitations and future prospects of this novel and promising target.

Keywords: brain-type glycogen phosphorylase (PYGB); glycogen metabolism; glycogen phosphorylase; pathology of diseases

DOI: https://doi.org/10.3390/cells13030289

J Mol Cell Cardiol. 2024 Feb;pii: S0022-2828(23)00195-5. [Epub ahead of print]187 90-100

Pluripotent stem cell-based cardiac regenerative therapy for heart failure.

Yusuke Soma, Hidenori Tani, Yuika Morita-Umei, Yoshikazu Kishino, Keiichi Fukuda, Shugo Tohyama.

Cardiac regenerative therapy using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is expected to become an alternative to heart transplantation for severe heart failure. It is now possible to produce large numbers of human pluripotent stem cells (hPSCs) and eliminate non-cardiomyocytes, including residual undifferentiated hPSCs, which can cause teratoma formation after transplantation. There are two main strategies for transplanting hPSC-CMs: injection of hPSC-CMs into the myocardium from the epicardial side, and implantation of hPSC-CM patches or engineered heart tissues onto the epicardium. Transplantation of hPSC-CMs into the myocardium of large animals in a myocardial infarction model improved cardiac function. The engrafted hPSC-CMs matured, and microvessels derived from the host entered the graft abundantly. Furthermore, as less invasive methods using catheters, injection into the coronary artery and injection into the myocardium from the endocardium side have recently been investigated. Since transplantation of hPSC-CMs alone has a low engraftment rate, various methods such as transplantation with the extracellular matrix or non-cardiomyocytes and aggregation of hPSC-CMs have been developed. Post-transplant arrhythmias, imaging of engrafted hPSC-CMs, and immune rejection are the remaining major issues, and research is being conducted to address them. The clinical application of cardiac regenerative therapy using hPSC-CMs has just begun and is expected to spread widely if its safety and efficacy are proven in the near future.

Keywords: Cardiomyocyte; Cell transplantation; Embryonic stem cell; Heart failure; Induced pluripotent stem cell; Regenerative therapy

DOI: https://doi.org/10.1016/j.yjmcc.2023.12.001

Front Mol Biosci. 2024 ;11 1365107

Editorial: Metabolomics in genetic and endocrinological diseases.

Mohamed Abu-Farha, Hicham Benabdelkamel, Fabio Mazzotti, Anas M Abdel Rahman.

Keywords: DNA methylation; NAFLD; lipidomics; mass spectrometry; metabolomics

DOI: https://doi.org/10.3389/fmolb.2024.1365107

Genet Med. 2024 Feb 05. pii: S1098-3600(24)00030-3. [Epub ahead of print] 101097

Biallelic loss-of-function variants of SLC12A9 cause lysosome dysfunction and a syndromic neurodevelopmental disorder.

PURPOSE: Pathogenic variants of FIG4 generate enlarged lysosomes and neurological and developmental disorders. To identify additional genes regulating lysosomal volume, we carried out a genome-wide activation screen to detect suppression of enlarged lysosomes in FIG4-/- cells.
METHODS: The CRISPR-a gene activation screen utilized sgRNAs from the promoters of protein coding genes. Fluorescence-activated cell sorting separated cells with correction of the enlarged lysosomes from uncorrected cells. Patient variants of SLC12A9 were identified by exome or genome sequencing and studied by segregation analysis and clinical characterization.
RESULTS: Overexpression of SLC12A9, a solute co-transporter, corrected lysosomal swelling in FIG4-/- cells. SLC12A9 (NP_064631.2) co-localized with LAMP2 at the lysosome membrane. Biallelic variants of SLC12A9 were identified in three unrelated probands with neurodevelopmental disorders. Common features included intellectual disability, skeletal and brain structural abnormalities, congenital heart defects and hypopigmented hair. Patient 1 was homozygous for nonsense variant p.(Arg615*); patient 2 was compound heterozygous for p.(Ser109Lysfs*20) and a large deletion, and proband 3 was compound heterozygous for p.(Glu290Glyfs*36) and p.(Asn552Lys). Fibroblasts from proband 1 contained enlarged lysosomes that were corrected by wildtype SLC12A9 cDNA. Patient variant p.(Asn552Lys) failed to correct the lysosomal defect.
CONCLUSIONS: Impaired function of SLC12A9 results in enlarged lysosomes and a recessive disorder with a recognizable neurodevelopmental phenotype.

Keywords: SLC12A9; co-transporter; lysosome; neurodevelopmental disorder; osmoregulation

DOI: https://doi.org/10.1016/j.gim.2024.101097