Rigid spine syndrome is a rare childhood-onset myopathy characterised by scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. The underlying genetic cause in some patients remains unexplained.
Using exome and genome sequencing, we identified biallelic variants in HMGCS1 (HMG-CoA synthase) in five patients from four unrelated families with genetically unresolved rigid spine syndrome. These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity, 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 core-like regions, occasional internal nuclei and rimmed vacuoles.
HMGCS1 encodes a key enzyme of the mevalonate pathway, disturbance of which is associated with HMGCR-related and GGPS1-related muscular dystrophy. HMGCS1 levels in skeletal muscle were comparable between healthy controls and the index case with a homozygous p.(S447P) substitution. Muscle RNA-seq for a patient with a frameshift variant (c.344_345del:p.S115Wfs*12) and an in trans substitution (p.(Q29L)) showed HMGCS1 transcript levels reduced to 53% compared to controls. The substitution appeared homozygous on RNA-seq, suggesting the allele harbouring the frameshift variant undergoes nonsense mediated decay.
hmgcs1-/- zebrafish displayed severe early defects, including immobility at 2 days and death by days 3 post-fertilisation. Given most patients in our cohort survived to adulthood, we anticipate the identified variants have subtle effects on HMGCS1 function. Correspondingly, analyses of recombinant human HMGCS1 and four mutants (p.S447P, p.Q29L, p.M70T, p.C268S) showed comparable secondary structures, dimerization, and enzymatic activity to the wildtype. Thermal stability of the mutants was similar or slightly reduced compared to the wildtype. Altogether, we suggest that the identified missense variants in HMGCS1 act through a hypomorphic mechanism to be elucidated.
This is the first association of HMGCS1 with Mendelian disease.