Bielas, S. | Search bioRxiv

bioRxiv2026

Donor-matched iPSC model reveals context-dependent T2D genetic signals in fibro-adipogenic progenitors

Fibro-adipogenic progenitors (FAPs) in skeletal muscle have been implicated in type 2 diabetes (T2D), yet their heterogeneity and context-dependent regulation remain poorly understood. Here, we establish induced pluripotent stem cell (iPSC)-derived FAPs as a model of primary FAPs by leveraging a unique resource: iPSC lines and skeletal muscle biopsies obtained from 34 individuals, a subset of 30 profiled using single-nucleus multiomics. Donor-matched comparisons reveal iPSC-FAPs recapitulate the transcriptome, epigenome, and subtype composition of primary FAPs. Using single-nucleus multiomics, we show that high-insulin exposure drives iPSC-FAPs toward an adipogenic fate - and this adipogenic subtype is enriched for T2D GWAS signals, an enrichment undetectable at baseline. We map the T2D-associated rs3814707 non-coding signal to LTBP3, a gene that influences FAP adipogenic differentiation. These findings reveal how disease-relevant regulatory mechanisms can be masked in unstimulated cells and establish iPSC-FAPs as a powerful platform for dissecting the state-dependent biology of complex metabolic disease.

genetics↗

bioRxiv2016

Homozygous c.259G>A variant in ISCA1 is associated with a new multiple mitochondrial dysfunctions syndrome

The iron-sulfur (Fe-S) cluster (ISC) biogenesis pathway is indispensable for many fundamental biological processes and pathogenic variations in genes encoding several components of the Fe-S biogenesis machinery, such as NFU1, BOLA3, IBA57 and ISCA2 are already implicated in causing four types of multiple mitochondrial dysfunctions syndromes (MMDS) among other human diseases. MMDS are clinically characterized by neurodevelopmental delay, neurological deterioration, lactic acidosis, extensive white matter abnormalities and early death. We report on two unrelated families, with two affected children each with neurodevelopmental delay, regression of developmental milestones, seizures, extensive white matter abnormalities, cortical migrational abnormalities, lactic acidosis and early demise. Exome sequencing of two affected individuals, one from each family, revealed a homozygous c.259G>A variant in ISCA1 and Mendelian segregation was confirmed in both families. ISCA1 is a specialized factor known to mediate maturation of distinct Fe-S cluster (ISC) proteins. In silico functional analyses and structural modeling of the protein predict the identified ISCA1 variant to be detrimental to protein stability and function. Notably the phenotype observed in all affected subjects with the ISCA1 pathogenic variant is similar to that previously described in all 4 types of MMDS. The ISCA1 variant lies in the only shared region of homozygosity between the two families suggesting the possibility of a founder effect. To the best of our knowledge this is the first instance where ISCA1 deficiency has been shown to be associated with a human disease, a new type of multiple mitochondrial dysfunctions syndrome.

genetics↗