ABSTRACT:

The sheep major histocompatibility complex (Mhc) was first identified 15 years ago by serological studies of sheep lymphocyte antigens. 1 Since then both classical class I and class II molecules have been identified as membrane-associated molecules (antigens) on sheep peripheral blood lymphocytes by serological and immunochemical methods. The relative paucity of international resources has meant that serological characterization of the sheep Mhc has been slow. In recent years the emphasis has moved to the use of the molecular techniques to characterize the ovine Mhc region. Relative to other domesticated species the ovine Mhc is poorly characterized. To date the class II region has been the focus for most investigations while the class I region has received little attention since the early flurry of serological effort. The presence of a class III region is still imputed by analogy with other ungulate species.

The sheep Mhc was initially termed OLA (ovine lymphocyte antigens) and is still referred to occasionally by this name, as a reflection of its serological history. However, to strengthen efforts for a systematic nomenclature of the Mhc in all vertebrates, 2 the sheep Mhc will be referred to as Ovar (from Ov is aries) in this chapter. The ovine Mhc has been mapped to chromosome 20q15-q23. 3 , 4 Although no overall physical map exists so far, information from overlapping cosmids and linkage analysis studies indicate similarities of the Ovar complex to cattle and human 5 , 6 (Groth and Wetherall, unpublished data; Crawford et al., unpublished data).

Schwaiger, F. W., J. Maddox, K. Ballingall, J. Buitkamp, A. M. Crawford, B. M. Dutia, J. T. Epplen, E. D. Ferguson, D. Groth, J. Hopkins, and 4 more contributors. 2026. The Ovine Major Histocompatibility Complex." In Major Histocompatibility Complex Region of Domestic Animal Species, 121-176

ABSTRACT:

Rigid spine syndrome is a rare childhood-onset myopathy characterized by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis.

In five patients from four unrelated families, we identified biallelic variants in HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorso-lumbar regions, scoliosis and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles.

HMGCS1 encodes a critical enzyme of the mevalonate pathway and has not yet been associated with disease. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy resembling our cohort’s presentation. Analyses of recombinant human HMGCS1 protein and four variants (p.S447P, p.Q29L, p.M70T, p.C268S) showed that all mutants maintained their dimerization state. Three of the four mutants exhibited reduced thermal stability, and two mutants showed subtle changes in enzymatic activity compared to the wildtype.

Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by Day 3 post-fertilisation and were rescued by HMGCS1 mRNA. We demonstrate that the four variants tested (S447P, Q29L, M70T and C268S) have reduced function compared to wild-type HMGCS1 in zebrafish rescue assays. Additionally, we demonstrate the potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish. Overall, our analyses suggest that these missense variants in HMGCS1 act through a hypomorphic mechanism.

Here, we report an additional component of the mevalonate pathway associated with disease and suggest biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine myopathy phenotype. Additionally, we highlight mevalonoic acid supplementation as a potential treatment for patients with HMGCS1-related disease.

Dofash, L. N. H., L. B. Miles, Y. Saito, E. Rivas, V. Calcinotto, S. Oveissi, R. J. Serrano, R. Templin, G. Ramm, A. Rodger, and 31 more contributors. 2025. HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model. Brain 148 (5): 1707-1722.