Yıl 2020, Cilt 3 , Sayı 3, Sayfalar 102 - 113 2020-11-05

Non-amiloidojenik Transtiretin Gen Varyantlarının Biyoinformatik Analizi ve His90Asn Varyantının Klinik Önemi
Bioinformatic Analysis of Non-Amyloidogenic Transtyhretin Gene Variants and Clinical Importance of His90Asn Variant

Evrim KÖMÜRCÜ BAYRAK [1] , Gizem ÇELEBİ [2] , Elif EROĞLU [3] , Gökhan KAHVECİ [4] , Fatih BAYRAK [5]


Amaç: Transtiretin (TTR) amiloidozu, otozomal dominant kalıtımlı değişken penetransa sahip bir hastalıktır. TTR genindeki patojenik varyantlar, TTR proteininin yanlış katlanmasına yol açarak kardiyomiyositlerde birikime ve kalp yetmezliğine sebep olabilmektedir. Bu çalışmada, biventriküler konsantrik hipertrofisi olan hastada TTR geninde saptanan His90Asn (H90N) varyantının hastalık patogenezine etkisinin ve non-amiloidojenik varyantlarının biyoinformatik analizlerle klinik önemlerinin belirlenmesi amaçlandı. Gereç ve Yöntem: İndeks vaka, 18 yıl kardiyolojik açıdan takip edildi ve Illumina TruSight Kardiyomiyopati paneli kapsamında 46 genin ekzonik bölgelerindeki varyantlar araştırıldı. TTR geninde H90N varyantı saptanan vakadan klinik olarak amiloidoz şüphesi ile rektal biopsi örneği alındı. Bu varyant, Sanger dizileme yöntemi ile konfirme edildi. Bulgular: Onbir yıl önce tanı alan ve ICD implante edilen 32 yaşındaki bir erkek vakada TTR geninin ekzon 3'ünde H90N varyantı heterozigot olarak belirlendi. Indeks vaka, kardiyak amiloidoz açısından değerlendirildiğinde, progresif sistolik disfonksiyona sahip olduğu (sol ventrikül ejeksiyon fraksiyonu, 2013'te %60, 2016'da %35 ve 2017'de %20) ve amiloidoz ile uyumlu epikardiyal ve endokardiyal tabakalarda global longutidunal strain (GLS) skoru ve strain rate değerinin azaldığı belirlendi. Rektal biyopsininde kongo kırmızısı boyamasında amiloid birikimi gözlenmedi. Bu varyant, asemptomatik olan babasında da tespit edildi. İlk defa bu çalışmada, TTR genindeki non-amiloidojenik aminoasit değişimine neden olan tüm varyantlar biyoinformatik analizlerle karşılaştırıldı. Sonuç: Bu çalışmada, H90N varyantının infiltratif miyokard hastalığındaki patojenik etkisi kanıtlanamamış olsada TTR genindeki H90N varyantı gibi non-amiloidojenik varyantların klinik değerlendirmede dikkate alınması gerektiği ortaya konmuştur.
Objective: Transthyretin (TTR) amyloidosis is an autosomal dominant inherited disease with variable penetration. Cardiac deposition of misfolded TTR protein due to missense pathogenic variants causes heart failure. Our aim was to determine the effect of the TTR gene His90Asn (H90N) variant on the pathogenesis of disease in a patient with biventricular concentric hypertrophy, and the clinical significance of variants defined as non-amyloidogenic with bioinformatic analysis. Materials and Methods: The index case was followed cardiologically for 18 years and pathogenic variants were investigated in the exonic regions of 46 genes using the Illumina TruSight Cardiomyopathy panel. Rectal biopsy specimen was taken from a case where the H90N variant was detected in the TTR gene, with clinical suspicion of amyloidosis. This variant was confirmed by the Sanger sequencing method. Results: Heterozygote H90N variant was determined in exon3 of the TTR gene in index case of a 32-year-old man with severe heart failure who was diagnosed 11 years ago and implanted with an ICD. He had progressive systolic dysfunction (left ventricular ejection fraction, 60% in 2013, 35% in 2016, and 20% in 2017). GLS score and strain rate were reduced in the epicardial and endocardial layers compatible with amyloidosis in the patient. In congo red staining of rectal biopsy, amyloid deposition was not observed. This variant was detected also in the patient’s father, who did not have clinical symptoms. For the first time in this study, all variants that cause non-amyloidogenic amino acid subtitutions in the TTR gene were compared with bioinformatics analyzes. Conclusion: In this study, although the pathogenic effect of the H90N variant in infiltrative myocardial disease was not proven, it was revealed that non-amyloidogenic variants such as the H90N variant in the TTR gene should be considered in clinical evaluation.
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Birincil Dil tr
Konular Tıp
Bölüm Research Article
Yazarlar

Orcid: 0000-0003-1271-1208
Yazar: Evrim KÖMÜRCÜ BAYRAK (Sorumlu Yazar)
Kurum: İSTANBUL ÜNİVERSİTESİ
Ülke: Turkey


Orcid: 0000-0002-7129-3045
Yazar: Gizem ÇELEBİ
Kurum: İSTANBUL ÜNİVERSİTESİ, AZİZ SANCAR DENEYSEL TIP ARAŞTIRMA ENSTİTÜSÜ
Ülke: Turkey


Orcid: 0000-0001-6700-9390
Yazar: Elif EROĞLU
Kurum: ACIBADEM MEHMET ALİ AYDINLAR ÜNİVERSİTESİ
Ülke: Turkey


Orcid: 0000-0001-8367-6505
Yazar: Gökhan KAHVECİ
Kurum: İstanbul Kartal Koşuyolu Yüksek İhtisas Eğitim ve Araştırma Hastanesi
Ülke: Turkey


Orcid: 0000-0002-1574-1085
Yazar: Fatih BAYRAK
Kurum: ACIBADEM MEHMET ALİ AYDINLAR ÜNİVERSİTESİ
Ülke: Turkey


Destekleyen Kurum İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi
Proje Numarası 42173 ve TDP-2017-22581
Tarihler

Başvuru Tarihi : 16 Eylül 2020
Kabul Tarihi : 13 Ekim 2020
Yayımlanma Tarihi : 5 Kasım 2020

APA Kömürcü Bayrak, E , Çelebi̇, G , Eroğlu, E , Kahveci̇, G , Bayrak, F . (2020). Non-amiloidojenik Transtiretin Gen Varyantlarının Biyoinformatik Analizi ve His90Asn Varyantının Klinik Önemi . Sağlık Bilimlerinde İleri Araştırmalar Dergisi , 3 (3) , 102-113 . Retrieved from https://dergipark.org.tr/tr/pub/sabiad/issue/57700/795625