LMF1 frameshift deletion in Franches-Montagnes horses with hypertriglyceridemia-induced pancreatitis.
Abstract: Hypertriglyceridemia (HTG) may be inherited and caused by variants in genes encoding enzymes of lipid metabolism. This study was prompted by the observation of eight Franches-Montagnes (FM) foals showing elevated plasma triglyceride levels and episodes of fatal acute pancreatitis. We termed this phenotype hypertriglyceridemia-induced pancreatitis (HIP). The affected foals were distantly related and inbred to a prominent stallion suggesting autosomal recessive inheritance. Whole genome sequencing of an affected foal identified a homozygous loss of function variant in LMF1 encoding lipase maturation factor 1. The variant, XM_023616679.1:c.369_373delinsTCT, leads to an early frameshift and is predicted to alter or truncate 78% of the LMF1 coding sequence. We genotyped the variant in a cohort of 2122 FM horses and identified 11 homozygous mutant animals including all eight foals that had initially been identified based on their clinical presentation. The three additional homozygous mutant animals had a comparable phenotype and were inbred to the same stallion. We concluded that all 11 had been affected by the same disease. Thus, we found perfect genotype-phenotype association in the tested cohort. The carrier frequency in the 2111 unaffected FM horses was 15.0%. Our findings enable genetic testing to prevent the unintentional breeding of further HIP-affected foals.
© 2025. The Author(s).
Publication Date: 2025-08-06 PubMed ID: 40764662PubMed Central: PMC12326015DOI: 10.1038/s41598-025-13954-9Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.
The research study investigates a particular type of horse known as Franches-Montagnes (FM) which suffer from a condition termed hypertriglyceridemia-induced pancreatitis (HIP). The condition, which triggers fatal acute pancreatitis due to elevated plasma triglyceride levels, was found to be linked to genetic mutations, specifically a loss-of-function variant in LMF1 gene which encodes lipase maturation factor 1. The study envisions to prevent the breeding of HIP-affected foals through genetic testing.
Research Purpose and Background
- The researchers embarked on this study after identifying eight Franches-Montagnes (FM) foals experiencing increased plasma triglyceride levels and episodes of deadly acute pancreatitis.
- In order to explore the origins of the disease, the researchers considered the possibility of genetic inheritance, as the affected foals were distantly related and inbred to a prominent stallion. This suggested an autosomal recessive inheritance pattern.
Genomic Examination and Discovery of a Genetic Variant
- A whole genome sequencing of an affected foal was done to pinpoint any possible genetic abnormalities. The sequencing revealed a homozygous loss-of-function variant in the LMF1 gene, which encodes lipase maturation factor 1.
- Additionally, the researchers found a variant, named XM_023616679.1:c.369_373delinsTCT, that led to an early frameshift predicted to alter or truncate 78% of the LMF1 coding sequence, potentially causing the hypertriglyceridemia-induced pancreatitis.
Disease Association and Genotyping
- The variant was genotyped in a cohort of 2122 FM horses, resulting in 11 horses being identified as homozygous mutant animals, confirming the genetic variant’s association with the disease.
- These included all eight foals initially identified due to their clinical condition, as well as three additional animals with a similar phenotype and a common ancestry to the same stallion.
Genotype-Phenotype Relationship and Carrier Frequency
- Based on the findings, the researchers were able to draw a perfect genotype-phenotype association in the sample cohort.
- The study revealed a 15% carrier frequency amongst 2111 unaffected FM horses.
Conclusions and Implications
- The research affirms that the disease found in the FM horses is genetic in nature due to the connection with the LMF1 variant discovered.
- The findings support enabling genetic testing as a preventive measure to avoid continued breeding of HIP-affected foals thereby preventing the propagation of this fatal genetic condition.
Cite This Article
APA
Drögemüller M, Fouché N, Wyler M, Gurtner C, Meister SL, Neuditschko M, Jagannathan V, Gerber V, Leeb T.
(2025).
LMF1 frameshift deletion in Franches-Montagnes horses with hypertriglyceridemia-induced pancreatitis.
Sci Rep, 15(1), 28667.
https://doi.org/10.1038/s41598-025-13954-9 Publication
Researcher Affiliations
- Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Swiss Institute of Equine Medicine, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Swiss Institute of Equine Medicine, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Animal GenoPhenomics, Agroscope, Route de la Tioleyre 4, 1725, Posieux, Switzerland.
- Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Swiss Institute of Equine Medicine, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland.
- Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Bern, Switzerland. tosso.leeb@unibe.ch.
MeSH Terms
- Animals
- Horses
- Hypertriglyceridemia / genetics
- Hypertriglyceridemia / veterinary
- Hypertriglyceridemia / complications
- Pancreatitis / genetics
- Pancreatitis / veterinary
- Pancreatitis / etiology
- Horse Diseases / genetics
- Horse Diseases / pathology
- Frameshift Mutation
- Male
- Homozygote
- Phenotype
- Genetic Association Studies
- Female
Grant Funding
- 627003244 / Bundesamt fu00fcr Landwirtschaft
- 627003244 / Bundesamt fu00fcr Landwirtschaft
- 627003244 / Bundesamt fu00fcr Landwirtschaft
- 627003244 / Bundesamt fu00fcr Landwirtschaft
Conflict of Interest Statement
Declarations. Competing interests: The authors declare no competing interests.
References
This article includes 25 references
- Hegele RA. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.. 655–666 (2014).
- Alves M. Understanding hypertriglyceridemia: integrating genetic insights.. 190 (2024).
- Pennacchio LA. An Apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing.. 169–173 (2001).
- Fojo SS. Donor splice site mutation in the Apolipoprotein (apo) C-II gene (apoC-II-Hamburg) of a patient with apoC-II deficiency.. 1489–1494 (1988).
- Wang J, Hegele RA. Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650).. 23 (2007).
- Benlian P. Complete paternal isodisomy for chromosome 8 unmasked by lipoprotein lipase deficiency.. 431–436 (1996).
- Peterfy M. Mutations in cause combined lipase deficiency and severe hypertriglyceridemia.. 1483–1487 (2007).
- Ginzinger DG. A mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia in a colony of domestic cats.. 1257–1266 (1996).
- Gmel AI. Using high-density SNP data to unravel the origin of the Franches-Montagnes horse breed.. 53 (2024).
- Haechler S. Congenital hepatic fibrosis and cystic bile duct formation in Swiss Freiberger horses.. 669–671 (2000).
- Drögemüller M. Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.. e110125 (2014).
- Verordnung über die Tierzucht [Animal Breeding Ordinance] URL. https://www.fedlex.admin.ch/eli/cc/2012/763/de; accessed 17-July-2025.
- Jagannathan V. A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves.. 695–704 (2019).
- McKenna A. The genome analysis toolkit: A mapreduce framework for analyzing next-generation DNA sequencing data.. 1297–1303 (2010).
- Jagannathan V. Comprehensive characterization of horse genome variation by whole-genome sequencing of 88 horses.. 74–77 (2019).
- Cingolani P. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff.. 80–92 (2012).
- Berryhill EH. Triglyceride concentrations in neonatal foals: serial measurement and effects of age and illness.. 23–29 (2017).
- Wu SA. Lipoprotein lipase and its regulators: an unfolding story.. 48–61 (2021).
- Babilonia-Rosa MA, Neher SB. Purification, cellular levels, and functional domains of lipase maturation factor 1.. 423–428 (2014).
- Paterniti JR. Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse.. 167–169 (1983).
- Cefalu AB. Novel LMF1 nonsense mutation in a patient with severe hypertriglyceridemia.. 4584–4590 (2009).
- Tanaka M. A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis.. 327–331 (2023).
- Cao C. Identification of a compound heterozygous LMF1 variants in a patient with severe hypertriglyceridemia - case report and literature review.. 1106–1111 (2024).
- Chyzyk V, Brown AS. Familial chylomicronemia syndrome: A rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis.. 80–85 (2020).
- Richards S. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.. 405–424 (2015).
Citations
This article has been cited 0 times.Use Nutrition Calculator
Check if your horse's diet meets their nutrition requirements with our easy-to-use tool Check your horse's diet with our easy-to-use tool
Talk to a Nutritionist
Discuss your horse's feeding plan with our experts over a free phone consultation Discuss your horse's diet over a phone consultation
Submit Diet Evaluation
Get a customized feeding plan for your horse formulated by our equine nutritionists Get a custom feeding plan formulated by our nutritionists
