Functional validation of novel variants in B4GALNT1 associated with early-onset complex hereditary spastic paraplegia with impaired ganglioside synthesis.
Julian Emanuel AlecuYuhsuke OhmiRobiul H BhuiyanKei-Ichiro InamoriTakahiro NittaAfshin SaffariHellen JumoMarvin ZieglerClaudio Melo de GusmaoNutan SharmaShiho OhnoNoriyoshi ManabeYoshiki YamaguchiMariko KambeKeiko FurukawaMustafa SahinJin-Ichi InokuchiKoichi FurakawaDarius Ebrahimi-FakhariPublished in: American journal of medical genetics. Part A (2022)
Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.
Keyphrases
- intellectual disability
- copy number
- cerebral palsy
- early onset
- botulinum toxin
- autism spectrum disorder
- high resolution
- upper limb
- genome wide
- single cell
- late onset
- healthcare
- dna methylation
- induced apoptosis
- multiple sclerosis
- case control
- high throughput
- photodynamic therapy
- cell cycle arrest
- single molecule
- heat shock protein
- small molecule
- heat stress
- amino acid
- extracellular matrix
- oxidative stress
- mass spectrometry
- circulating tumor cells
- cell wall
- bone marrow
- clinical evaluation
- rotator cuff