An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Ferdinandusse Sacha, McWalter Kirsty, Te Brinke Heleen, IJlst Lodewijk, Mooijer Petra M, Ruiter Jos P N, van Lint Alida E M, Pras-Raves Mia, Wever Eric, Millan Francisca, Guillen Sacoto Maria J, Begtrup Amber, Tarnopolsky Mark, Brady Lauren, Ladda Roger L, Sell Susan L, Nowak Catherine B, Douglas Jessica, Tian Cuixia, Ulm Elizabeth, Perlman Seth, Drack Arlene V, Chong Karen, Martin Nicole, Brault Jennifer, Brokamp Elly, Toro Camilo, Gahl William A, Macnamara Ellen F, Wolfe Lynne, Undiagnosed Diseases Network, Waisfisz Quinten, Zwijnenburg Petra J G, Ziegler Alban, Barth Magalie, Smith Rosemarie, Ellingwood Sara, Gaebler-Spira Deborah, Bakhtiari Somayeh, Kruer Michael C, van Kampen Antoine H C, Wanders Ronald J A, Waterham Hans R, Cassiman David, Vaz Frédéric M
Аннотация
METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.
RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.
CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.