Obsl1-KO Mouse

Obsl1, or obscurin-like 1, is a gene with diverse functions. It is part of the obscurin protein family, and its members play roles in muscle-related processes such as sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism. In neurons, it is involved in the regulation of Golgi morphology and dendrite patterning through an OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism [2,4].

Global Obsl1 knockout mice are embryonically lethal, while skeletal muscle-specific Obsl1 knockouts show a benign phenotype similar to obscurin knockouts. Only when both obscurin and Obsl1 are deleted, their roles in sarcolemmal stability and sarcoplasmic reticulum organization become evident. Also, combined loss of Obsc and Obsl1 in murine hearts leads to diastolic dysfunction, altered metabolism, and deregulated mitophagy [2,5]. In humans, mutations in OBSL1 cause 3M Syndrome 2 (3M2), a growth retardation disorder with characteristic facial dysmorphism and musculoskeletal abnormalities. A study on a Pakistani kinship with a syndrome including short stature and other features identified a homozygous OBSL1 c.848delG mutation as the causal variant, expanding the known clinical phenotype of 3M2 [1]. In a Chinese patient with 3M syndrome, compound heterozygote mutations in OBSL1 were found, with c.458dupG potentially being a hotspot mutation in the Chinese population [3].

In conclusion, Obsl1 is crucial for muscle membrane systems, cardiac function, and normal growth. Gene knockout models in mice have been instrumental in revealing its functions in muscle and cardiac biology, while human studies of OBSL1 mutations have enhanced our understanding of growth-related disorders like 3M syndrome.

References:

1. Koprulu, Mine, Shabbir, Rana Muhammad Kamran, Mumtaz, Sara, Tolun, Aslıhan, Malik, Sajid. 2023. Expanding OBSL1 Mutation Phenotype: Disproportionate Short Stature, Barrel Chest, Thoracic Kyphoscoliosis, Hypogonadism, and Hypospadias. In The Yale journal of biology and medicine, 96, 367-382. doi:10.59249/RLAU6003. https://pubmed.ncbi.nlm.nih.gov/37780995/

2. Blondelle, Jordan, Marrocco, Valeria, Clark, Madison, Ghassemian, Majid, Lange, Stephan. 2019. Murine obscurin and Obsl1 have functionally redundant roles in sarcolemmal integrity, sarcoplasmic reticulum organization, and muscle metabolism. In Communications biology, 2, 178. doi:10.1038/s42003-019-0405-7. https://pubmed.ncbi.nlm.nih.gov/31098411/

3. Piao, Yurong, Li, Rongmin, Wang, Yingjie, Chen, Congli, Sang, Yanmei. 2024. Novel OBSL1 Variant in a Chinese Patient with 3M Syndrome: The c.458dupG Mutation May Be a Potential Hotspot Mutation in the Chinese Population. In Journal of clinical research in pediatric endocrinology, 16, 501-506. doi:10.4274/jcrpe.galenos.2024.2023-11-6. https://pubmed.ncbi.nlm.nih.gov/38407006/

4. Litterman, Nadia, Ikeuchi, Yoshiho, Gallardo, Gilbert, Harper, J Wade, Bonni, Azad. 2011. An OBSL1-Cul7Fbxw8 ubiquitin ligase signaling mechanism regulates Golgi morphology and dendrite patterning. In PLoS biology, 9, e1001060. doi:10.1371/journal.pbio.1001060. https://pubmed.ncbi.nlm.nih.gov/21572988/

5. Fujita, Kyohei, Desmond, Patrick, Blondelle, Jordan, Börgeson, Emma, Lange, Stephan. 2025. Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy. In Circulation. Heart failure, 18, e011867. doi:10.1161/CIRCHEARTFAILURE.124.011867. https://pubmed.ncbi.nlm.nih.gov/40066567/