SPAST Geninde De Novo Missense Mutasyonu Olan Spastik Parapleji Tip 4’lü Bir Türk Hasta

Öz

Otozomal dominant kalıtsal spastik paraplejilerin yaygın bir formu, SPAST genindeki mutasyonlardan kaynaklanan spastik parapleji tip 4'tür. Bu araştırmada, HSP'nin patofizyolojisi için ek genetik kanıt sağlamak amacıyla bir Türk SPG4 hastasının SPAST genotipi ve klinik fenotipi analiz edildi. Vaka Sunumu: Probandın ve aile üyelerinin klinik verileri toplandı. Periferik kandan tüm genomik DNA izole edildikten sonra, genleri tanımlamak ve mutasyonların patojenitesini analiz etmek için tüm ekzom dizileme teknolojisi kullanıldı. Şüpheli patojenik mutasyonlar belirlendi. Bu aile için doğrulama Sanger dizilemesi ile gerçekleştirildi. SPAST gen dizilemesi sonucu de novo missense c.1496G > A (p.R499H) ve missense MEFV c.2177T>C (p.Val726Ala) mutasyonları belirlendi. SPAST mutasyonu ebeveynlerde ve akrabalarda yoktu. c.1496G > A mutasyonu SPAST'ta belirgin derecede yüksek oranlarda de novo varyant olarak ortaya çıktığı bilinmektedir. SPAST'ta p.Arg499His mutasyonu olan literatürde bildirilen hastaların klinik özelliklerini inceledik. Elde edilen kanıtlar, erken başlangıçlı HSP ile SPAST'taki p.Arg499His anlamsız mutasyonu arasında olası bir ilişki olduğunu göstermektedir. SPAST dizi analizi, patojenik mutasyonların çoğunun proteinin AAA kodunda meydana geldiğini ve bunun SPG4 patogenezi ile yakın bir ilişkide olabileceğini ortaya koymuştur. Bu araştırmanın sonuçları, SPAST'taki p.Arg499His mutasyonu için terapötik uygulama yelpazesini genişletebilir ve SPG4'ün genotip-fenotip ilişkisini daha ayrıntılı olarak araştırma şansı sunabilir.

Anahtar Kelimeler

• Spastik Parapleji Tip 4
• SPAST Geni
• Missense Mutasyon

A Turkish Patient with Spastic Paraplegia Type 4 with a De Novo Missense Mutation in the SPAST Gene

Öz

Spastic paraplegia type 4 is a common type of autosomal-dominant pure hereditary spastic paraplegia that is brought on by variations in the SPAST gene. In this investigation, the SPAST genotype and clinical phenotype of a Turkish SPG4 patient were analyzed in an effort to provide additional genetic evidence for the pathophysiology of HSP. The clinical data of the proband and his family members were collected. After complete genomic DNA was isolated from peripheral blood, whole-exome sequencing technology was used to identify genes and analyze the pathogenicity of variants. Variants suspected of being pathogenic were found. Within this family, Sanger sequencing was used for verification. The sequencing of SPAST revealed a de novo missense c.1496G > A (p.Arg499His) and missense MEFV c.2177T>C (p.Val726Ala) variants. The parents and paternal relatives did not have the SPAST mutation. De novo variants of the c.1496G > A mutation in SPAST can arise at notably high frequencies. We discussed the case of a Turkish patient and examined the clinical characteristics of patients with the p.Arg499His variation in SPAST that have been documented in the literature. There is growing evidence that the p.Arg499His missense mutation in SPAST may be linked to early-onset HSP. The majority of pathogenic mutations were found in the protein's AAA domain, according to analysis of SPAST sequences; this may be closely related to the pathophysiology of SPG4. The results of this investigation may broaden the range of therapeutic applications for the p.Arg499His mutation in SPAST and offer a chance to investigate the genotype-phenotype relationship of SPG4 in more detail.

Anahtar Kelimeler

• Spastic Paraplegia Type 4
• Missense Mutation
• SPAST Gene

Kaynakça

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