Abstract
ObjectiveWe proposed that the deficit of ACC1 is the cause of patient symptoms including global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. We evaluated the possible disease-causing role of the ACACA gene in developmental delay and investigated the pathogenesis of ACC1 deficiency.MethodsA patient who presented with global developmental delay with unknown cause was recruited. Detailed medical records were collected and reviewed. Whole exome sequencing found two variants of ACACA with unknown significance. ACC1 mRNA expression level, protein expression level, and enzyme activity level were detected in patient-derived cells. Lipidomic analysis, and in vitro functional studies including cell proliferation, apoptosis, and the migratory ability of patient-derived cells were evaluated to investigate the possible pathogenic mechanism of ACC1 deficiency. RNAi-induced ACC1 deficiency fibroblasts were established to assess the causative role of ACC1 deficit in cell migratory disability in patient-derived cells. Palmitate supplementation assays were performed to assess the effect of palmitic acid on ACC1 deficiency-induced cell motility deficit.ResultsThe patient presented with global developmental delay, microcephaly, hypotonia, and dysmorphic facial features. A decreased level of ACC1 and ACC1 enzyme activity were detected in patient-derived lymphocytes. Lipidomic profiles revealed a disruption in the lipid homeostasis of the patient-derived cell lines. In vitro functional studies revealed a deficit of cell motility in patient-derived cells and the phenotype was further recapitulated in ACC1-knockdown (KD) fibroblasts. The cell motility deficit in both patient-derived cells and ACC1-KD were attenuated by palmitate.ConclusionWe report an individual with biallelic mutations in ACACA, presenting global development delay. In vitro studies revealed a disruption of lipid homeostasis in patient-derived lymphocytes, further inducing the deficit of cell motility capacity and that the deficiency could be partly attenuated by palmitate.
Highlights
Acetyl-coenzyme A carboxylase (ACC) catalyzes the conversion of acetyl-CoA into malonyl-CoA (Hopwood and Sherman, 1990)
The birth history was obtained from the parents, the proband was born after a 40-week gestation via cesarean section due to premature rupture of membranes (PROM) and amniotic fluid contamination
Vitamin B2 was applied with the consideration of the symptoms of weakness, fatigue, etc., Levocarnitine was administered to attenuate the deficiency of serum carnitine
Summary
Acetyl-coenzyme A carboxylase (ACC) catalyzes the conversion of acetyl-CoA into malonyl-CoA (Hopwood and Sherman, 1990). Cytosolic protein ACC1 mainly exists in the liver and adipose tissue (Thampy, 1989) and is encoded by ACC alpha (ACACA, MIM: 200350). Mitochondrial membrane protein ACC2 mainly exists in the liver, heart, and skeletal muscle (Abu-Elheiga et al, 2000) and is encoded by ACC beta (ACACB, MIM:601557). The malonyl-CoA produced by ACC2 works as the inhibitor of carnitine palmitoyltransferase 1 (CPT1), and participates in the regulation of fatty acid oxidation (AbuElheiga et al, 2001). Both ACCs play essential roles in lipid metabolism
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