Screening of known disease genes in congenital scoliosis

Abstract

A LFNG mutation is reported in a case of spondylocostal dysostosis (SCD), a skeletal dysplasia with severe malformations of vertebra and rib. The CS patient with LFNG mutations had multiple vertebral malformations including hemivertebrae, butterfly vertebrae, and block vertebrae, and rib malformations. LFNG mutations may cause a spectrum of phenotypes including CS and SCD. The current list of known disease genes could explain only a small fraction of genetic cause of CS.

Clinical and molecular delineation of spondylocostal dysostosis type 3

“…(E) Schematic representation of LFNG gene and localization of published mutations in patients with SCDO3. [1][2][3][4] The variant described in this study is located in exon 2 of LFNG (NM_001040167. LFNG belongs to the Fringe genes encoding a family of glycosyltransferases in the Notch signaling pathway and is localized to the Golgi.…”

“…1 To date five patients with frameshift or missense variants in LFNG gene presenting with M-SDV were published. [1][2][3][4] Two individuals showed further minor nonspine-related anomalies (hernia, camptodactyly), but no major organ involvement has been described in SCDO3 patients so far.…”

Fgf4 maintains Hes7 levels critical for normal somite segmentation clock function

“…Mutations in nearly all of the aforementioned Notch pathway genes have been identified in human patients where defective somitogenesis is thought to be the cause of Segmentation Defects of the Vertebrae (SDV) ( Eckalbar et al, 2012 ; Giampietro et al, 2009 ). For example, frequently recessive mutations in DLL3 , HES7 , MESP2 and LFNG and a dominant mutation in TBX6 ( Sparrow et al, 2013 ; Lefebvre et al, 2017 ) have been identified in patients with spondylocostal dysostosis (SCDO), which is characterized by severe vertebral malformations that include hemivertebrae, vertebral loss and fusion along the length of the axis ( Takeda et al, 2018 ). Whereas SCDO is relatively rare, congenital scoliosis (CS), defined as a lateral curvature of the spine exceeding 10%, is much more common, with a frequency of 1:1000, which is suspected to be an underestimation because asymptomatic individuals do not seek medical care ( Giampietro et al, 2013 ).…”

“…Whereas SCDO is relatively rare, congenital scoliosis (CS), defined as a lateral curvature of the spine exceeding 10%, is much more common, with a frequency of 1:1000, which is suspected to be an underestimation because asymptomatic individuals do not seek medical care ( Giampietro et al, 2013 ). Mutated alleles of HES7 , LFNG , MESP2 , and TBX6 are all associated with CS ( Lefebvre et al, 2017 ; Takeda et al, 2018 ; Giampietro et al, 2013 ; Sparrow et al, 2012 ).…”

Effects of Notch glycosylation on health and diseases

“…The missense mutation exists in the DxD motif forming a catalytic site of the glycosyltransferase and causes loss of enzymatic activity of the mutant, suggesting that the disappearance of GlcNAcextension of O-fucose glycans likely causes SCD(Otomo et al, 2019).The recent screening of 78 patients with congenital scoliosis (CS) without a mutation in the known causative gene, TBX6, identified a patient with compound heterozygous missense variants in LFNG. The missense mutations, p.Leu156Arg and p.Arg286Trp, reported loss of the enzymatic activity(Takeda et al, 2018). Aberrant O-fucosylation may be involved in the pathogenesis of CS as well as SCD.…”