Characterization of novel TOR1A variants causing extreme phenotypes of arthrogryposis multiplex congenita

Pascher, Michael Thomas (2023): Characterization of novel TOR1A variants causing extreme phenotypes of arthrogryposis multiplex congenita. Dissertation, LMU München: Medizinische Fakultät

Abstract

The TOR1A gene encodes torsinA, an AAA+ ATPase that exerts multiple functions, including nuclear envelope homeostasis and regulation of centrosome orientation and cell migration. A single amino acid deletion (p.Glu303del) in torsinA causes a long-recognized low-penetrance autosomal dominant disorder, torsion dystonia-1. More recently, biallelic TOR1A variants have been linked to an additional condition, an autosomal recessive congenital arthrogryposis syndrome complicated by global developmental delay. This study extends the clinical and mutation spectrum of the TOR1A-associated contrac-ture syndrome: Four patients carried a homozygous variant c.862C>T (p.Arg288*) and presented with severe contractures, massive global developmental delays, generalized muscle weakness, bulbar dysfunction and respiratory failure. All four infants died within the first 11 weeks of life. One case with compound heterozygous variants c.-3G>T and c.336C>A (p.Ser112Arg) presented with a much milder phenotype consisting of congenital contractures, motor delay, spastic paraparesis and moderate cognitive deficits. Contractures largely improved over time and were only slightly debilitating when last examined at age eight years. Arthrogryposis-related TOR1A variants led to decreased cellular levels of torsinA. Low levels of the p.Ser112Arg and p.Arg288* variants seem to result from increased protein turnover by the proteasome. Conversely, the 5’-UTR variant c.-3G>T, affecting a highly conserved base in the TOR1A Kozak sequence, appears to affect protein levels by impairing translation efficiency. The p.Ser112Arg variant also altered torsinA subcellular localization, which may further reduce availability of torsinA at its site of physiological action. In patient-derived dermal fibroblasts, strong reduction of torsinA levels (homozygous p.Arg288*) impaired positioning of centrosomes and cell motility, consistent with disruption of known torsinA functions. In conclusion, biallelic TOR1A mutations alter properties of torsinA and its cellular func-tions and cause variable forms of arthrogryposis. Pathogenicity of TOR1A variants was supported by altered properties of mutant torsinA and torsinA-deficient patient-derived cells, even though it is still unclear how disruption of torsinA functions eventually leads to disease.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: TOR1A, AMC, arthrogryposis multiplex congenita, torsinA, DYT1, torsion dystonia-1, Torsionsdystonie Typ 1
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 13. Juli 2023
• 1. Bericht­erstatter:in: Senderek, Jan