bims-meglyc 2025-02-09 papers

Issue of 2025–02–09
three papers selected by
Silvia Radenkovic, UMC Utrecht

Iran J Child Neurol. 2025 ;19(1): 121-126

Rafiq Syndrome: Old Variant in MAN1B1 Gene and Some New Phenotypic Features.

Rafiq syndrome is a congenital disorder of glycosylation type II that develops due to mutations in the Mannosidase Alpha Class 1B Member 1 (MAN1B1) gene encoding α 1,2-mannosidase. In the literature, 45 patients have been reported to date. This study presents a patient with some phenotypic traits that differ from previously reported patients with Rafiq syndrome.Since the patient was not diagnosed despite detailed examinations, whole exome sequencing was performed. The patientss' homozygous c.1000 C>T (p.Arg334Cys) pathogenic variant was detected in the MAN1B1 gene (NM_016219.5), which was consistent with Rafiq syndrome. Our patient's clinical findings were mainly similar to those of previously reported patients. However, our patient had feeding difficulty that started to improve after the fifth month and persistent hyperekplexia . Feeding difficulty and hyperekplexia concomitant to MAN1B1 gene mutation are reported for the first time. More extensive case series are needed to understand whether these findings are part of the syndrome or incidental comorbid conditions.

Keywords: Congenital Disorder of Glycosylation; Gene Mutation; Hyperekplexia; Rafiq Syndrome MAN1B1

DOI: https://doi.org/10.22037/ijcn.v19i1.42376

Orphanet J Rare Dis. 2025 Jan 31. 20(1): 46

Heterozygous pathogenic STT3A variation leads to dominant congenital glycosylation disorders and functional validation in zebrafish.

Linxue Meng, Zhixu Fang, Li Jiang, Yinglan Zheng, Siqi Hong, Yu Deng, Lingling Xie.

BACKGROUND: Congenital disorders of glycosylation are a rare group of disorders characterized by impaired glycosylation, wherein STT3A encodes the catalytic subunit of the oligosaccharyltransferase complex, which is crucial for protein N-glycosylation. Previous studies have reported that STT3A-CDG is caused by autosomal recessive inheritance. However, in this study, we propose that STT3A-CDG can be pathogenic through autosomal dominant inheritance.
METHODS: The variant was identified via trio whole-exome sequencing. We constructed wild-type and variant plasmids, transfected them into HEK293T cells and detected the expression levels of the STT3A protein. We performed CRISPR-Cas9 to establish heterozygous knockdown zebrafish to validate the functional implications of autosomal dominant inheritance of STT3A in pathogenesis.
RESULTS: The patient presented with developmental delay, distinctive facial features, short stature, and abnormal discharges. The heterozygous pathogenic missense variant (NM_001278503.2: c.499G > T, NP_001265432.1:p. Asp167Tyr) was identified, and the Western blot results revealed a significant decrease in protein levels. Heterozygous knockdown zebrafish exhibit phenotypes similar to those of patients, including craniofacial dysmorphology (increased eye distance, increased Basihyal's length, increased Ceratohyal's angle), skeletal abnormalities (reduced number of mineralized bones), developmental delay (reduced adaptability under light‒dark stimuli suggesting abnormal locomotion, orientation, and social behavior), and electrophysiological abnormalities.
CONCLUSION: We report a proband with a dominant congenital glycosylation disorder caused by heterozygous pathogenic STT3A variation, which is a new inheritance pattern of STT3A. Our report expands the known phenotype of dominant STT3A-CDGs. Furthermore, we provide in vivo validation through the establishment of a heterozygous knockdown zebrafish model for stt3a and strengthened the compelling evidence for dominant STT3A-related pathogenesis.

Keywords: STT3A gene; Congenital glycosylation disorders; Dominant inheritance; Phenotype; Zebrafish

DOI: https://doi.org/10.1186/s13023-025-03557-y

Neurobiol Dis. 2025 Jan 30. pii: S0969-9961(25)00038-5. [Epub ahead of print] 106822

iPSC models of mitochondrial diseases.

Sonja Heiduschka, Alessandro Prigione.

Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.

Keywords: Brain organoids; Disease modeling; Drug discovery; Mitochondrial diseases; Pluripotent stem cells

DOI: https://doi.org/10.1016/j.nbd.2025.106822