Functional validation of novel variants in B4GALNT1 associated with early‐onset complex hereditary spastic paraplegia with impaired ganglioside synthesis

Autor: Julian Emanuel Alecu, Yuhsuke Ohmi, Robiul H. Bhuiyan, Kei‐ichiro Inamori, Takahiro Nitta, Afshin Saffari, Hellen Jumo, Marvin Ziegler, Claudio Melo de Gusmao, Nutan Sharma, Shiho Ohno, Noriyoshi Manabe, Yoshiki Yamaguchi, Mariko Kambe, Keiko Furukawa, Mustafa Sahin, Jin‐ichi Inokuchi, Koichi Furakawa, Darius Ebrahimi‐Fakhari
Rok vydání: 2022
Předmět:
Zdroj: American Journal of Medical Genetics Part A. 188:2590-2598
ISSN: 1552-4833
1552-4825
DOI: 10.1002/ajmg.a.62880
Popis: 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.532-1GC/c.1556GC (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.
Databáze: OpenAIRE
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