Non-amiloidojenik Transtiretin Gen Varyantlarının Biyoinformatik Analizi ve His90Asn Varyantının Klinik Önemi
Öz
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.
Anahtar Kelimeler
Destekleyen Kurum
İstanbul Üniversitesi Bilimsel Araştırma Projeleri Birimi
Proje Numarası
42173 ve TDP-2017-22581
Kaynakça
- 1. Riek R, Eisenberg DS. The activities of amyloids from a structural perspective. Nature 2016; 539(7628):227-35.
- 2. Angelini A, Zanco F, Castellani C, Di Francesco A, Barbera MD, Vescovo GM, et al. Cardiac amyloidosis: a review of the literature and a practical approach for the clinicians. Italian Journal of Medicine 2019; 13: 73-90.
- 3. Guan J, Mishra S, Falk RH, Liao R. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol 2012; 302(3):H544-H552.
- 4. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126(10): 1286-300.
- 5. Park GY, Jamerlan A, Shim KH, An SSA. Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases. Int J Mol Sci 2019;20(12):2982.
- 6. Kocabaş GÜ, Kocabaş U, Gültekin N. Kardiyak Amiloidoz; Patofizyoloji, Teşhis ve Tedavi. Gültekin N, editör. İnfiltratif Kardiyomiyopatiler, Lizozomal Depo Hastalıkları, Mitokondriyal ve Genetik Mutasyonlara Bağlı Kardiyomiyopatiler. Ankara: Türkiye Klinikleri 2018; p.11-22.
- 7. Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum Mutat 2001;17(6):493-503.
- 8. Date Y, Nakazato M, Kangawa K, Shirieda K, Fujimoto T, Matsukura S. Detection of three transthyretin gene mutations in familial amyloidotic polyneuropathy by analysis of DNA extracted from formalin-fixed and paraffin-embedded tissues. J Neurol Sci 1997;150(2):143-8.
- 9. Refetoff S, Marinov VS, Tunca H, Byrne MM, Sunthornthepvarakul T, Weiss RE. A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J Clin Endocrinol Metab 1996; 81(9):3335-40.
- 10. Jimenez-Zepeda VH, Bahlis NJ, Gilbertson J, Rendell N, Porcari R, Lachmann HJ, et al. A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred. Amyloid 2015;22(1):26-30.
- 11.Durmuş-Tekçe H, Matur Z, Mert Atmaca M, Poda M, Çakar A, Hıdır Ulaş Ü, et al. Genotypic and phenotypic presentation of transthyretinrelated familial amyloid polyneuropathy (TTRFAP) in Turkey. Neuromuscul Disord 2016; 26(7):441-6.
- 12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5):405-24.
- 13. Skare JC, Saraiva MJ, Alves IL, Skare IB, Milunsky A, Cohen AS, et al. A new mutation causing familial amyloidotic polyneuropathy. Biochem Biophys Res Commun 1989;164(3):1240-6.
- 14. Skare JC, Milunsky JM, Milunsky A, Skare IB, Cohen AS, Skinner M. A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90. Clin Genet 1991;39(1):6-12.
- 15. Skare J, Jones LA, Myles N, Kane K, Milunsky A, Cohen A, et al. Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis. Clin Genet 1994;45(6):281-4.
- 16. Ueno S, Uemichi T, Takahashi N, Soga F, Yorifuji S, Tarui S. Two novel variants of transthyretin identified in Japanese cases with familial amyloidotic polyneuropathy: transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg). Biochem Biophys Res Commun 1990; 169(3):1117-21.
- 17. Saraiva MJ, Almeida MR, Alves IL, Moreira P, Gawinowicz M, Costa PP, Rauh S, Banhzoff A, Altland K. Molecular analyses of an acidic transthyretin Asn 90 variant. Am J Hum Genet 1991;48(5):1004-8.
- 18. Altland K, Banzhoff A. Separation by hybridisoelectric focusing of normal human plasma transthyretin (prealbumin) and a variant with a methionine for valine substitution associated with familial amyloidotic polyneuropathy. Electrophoresis 1986; 7(11):529-33.
- 19. Altland K, Becher P, Banzhoff A. Paraffin oil protected high resolution hybridisoelectric focusing for the demonstration of substitutions of neutral amino acids in denatured proteins: the case off our human transthyretin (prealbumin) variants associated with familial amyloidotic polyneuropathy. Electrophoresis 1987;8(6): 293-7.
- 20. Alves IL, Almeida MR, Skare J, Skinner M, Kurose K, Sakaki Y, Costa PP, Saraiva MJ. Amyloidogenic and non-amyloidogenic transthyretin Asn 90 variants. Clin Genet 1992;42(1):27-30.
- 21. Alves IL, Divino CM, Schussler GC, Altland K, Almeida MR, Palha JA, et al. Thyroxine binding in a TTR Met 119 kindred. J Clin Endocrinol Metab 1993; 77(2):484-8.
- 22. Haagsma EB, Hawkins PN, Benson MD, Lachmann HJ, Bybee A, Hazenberg BP. Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American- Finnish families. Amyloid 2004;11(1):44-9.
- 23. Bersano A, Del Bo R, Ballabio E, Cinnante C, Lanfranconi S, Comi GP, et al. Transthyretin Asn90 variant: amyloidogenic or nonamyloidogenic role. J Neurol Sci. 2009; 284(1- 2):113-5.
- 24. Solov’ev KV, Grudinina NA, Semernin EN, Morozova IV, Smirnova SA, Poliakov DS, Aleĭnikova TD, Shliakhto EV, Gudkova AY, Shavlovskiĭ MM. Transthyretin gene V30M, H90N, and del9 mutations in cardiomyopathy patients from St. Petersburg. Genetika. 2011;47(4):543-9.
Bioinformatic Analysis of Non-Amyloidogenic Transtyhretin Gene Variants and Clinical Importance of His90Asn Variant
Öz
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.
Anahtar Kelimeler
Proje Numarası
42173 ve TDP-2017-22581
Kaynakça
- 1. Riek R, Eisenberg DS. The activities of amyloids from a structural perspective. Nature 2016; 539(7628):227-35.
- 2. Angelini A, Zanco F, Castellani C, Di Francesco A, Barbera MD, Vescovo GM, et al. Cardiac amyloidosis: a review of the literature and a practical approach for the clinicians. Italian Journal of Medicine 2019; 13: 73-90.
- 3. Guan J, Mishra S, Falk RH, Liao R. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol 2012; 302(3):H544-H552.
- 4. Ruberg FL, Berk JL. Transthyretin (TTR) cardiac amyloidosis. Circulation 2012; 126(10): 1286-300.
- 5. Park GY, Jamerlan A, Shim KH, An SSA. Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases. Int J Mol Sci 2019;20(12):2982.
- 6. Kocabaş GÜ, Kocabaş U, Gültekin N. Kardiyak Amiloidoz; Patofizyoloji, Teşhis ve Tedavi. Gültekin N, editör. İnfiltratif Kardiyomiyopatiler, Lizozomal Depo Hastalıkları, Mitokondriyal ve Genetik Mutasyonlara Bağlı Kardiyomiyopatiler. Ankara: Türkiye Klinikleri 2018; p.11-22.
- 7. Saraiva MJ. Transthyretin mutations in hyperthyroxinemia and amyloid diseases. Hum Mutat 2001;17(6):493-503.
- 8. Date Y, Nakazato M, Kangawa K, Shirieda K, Fujimoto T, Matsukura S. Detection of three transthyretin gene mutations in familial amyloidotic polyneuropathy by analysis of DNA extracted from formalin-fixed and paraffin-embedded tissues. J Neurol Sci 1997;150(2):143-8.
- 9. Refetoff S, Marinov VS, Tunca H, Byrne MM, Sunthornthepvarakul T, Weiss RE. A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J Clin Endocrinol Metab 1996; 81(9):3335-40.
- 10. Jimenez-Zepeda VH, Bahlis NJ, Gilbertson J, Rendell N, Porcari R, Lachmann HJ, et al. A novel transthyretin variant p.H110D (H90D) as a cause of familial amyloid polyneuropathy in a large Irish kindred. Amyloid 2015;22(1):26-30.
- 11.Durmuş-Tekçe H, Matur Z, Mert Atmaca M, Poda M, Çakar A, Hıdır Ulaş Ü, et al. Genotypic and phenotypic presentation of transthyretinrelated familial amyloid polyneuropathy (TTRFAP) in Turkey. Neuromuscul Disord 2016; 26(7):441-6.
- 12. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5):405-24.
- 13. Skare JC, Saraiva MJ, Alves IL, Skare IB, Milunsky A, Cohen AS, et al. A new mutation causing familial amyloidotic polyneuropathy. Biochem Biophys Res Commun 1989;164(3):1240-6.
- 14. Skare JC, Milunsky JM, Milunsky A, Skare IB, Cohen AS, Skinner M. A new transthyretin variant from a patient with familial amyloidotic polyneuropathy has asparagine substituted for histidine at position 90. Clin Genet 1991;39(1):6-12.
- 15. Skare J, Jones LA, Myles N, Kane K, Milunsky A, Cohen A, et al. Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis. Clin Genet 1994;45(6):281-4.
- 16. Ueno S, Uemichi T, Takahashi N, Soga F, Yorifuji S, Tarui S. Two novel variants of transthyretin identified in Japanese cases with familial amyloidotic polyneuropathy: transthyretin (Glu42 to Gly) and transthyretin (Ser50 to Arg). Biochem Biophys Res Commun 1990; 169(3):1117-21.
- 17. Saraiva MJ, Almeida MR, Alves IL, Moreira P, Gawinowicz M, Costa PP, Rauh S, Banhzoff A, Altland K. Molecular analyses of an acidic transthyretin Asn 90 variant. Am J Hum Genet 1991;48(5):1004-8.
- 18. Altland K, Banzhoff A. Separation by hybridisoelectric focusing of normal human plasma transthyretin (prealbumin) and a variant with a methionine for valine substitution associated with familial amyloidotic polyneuropathy. Electrophoresis 1986; 7(11):529-33.
- 19. Altland K, Becher P, Banzhoff A. Paraffin oil protected high resolution hybridisoelectric focusing for the demonstration of substitutions of neutral amino acids in denatured proteins: the case off our human transthyretin (prealbumin) variants associated with familial amyloidotic polyneuropathy. Electrophoresis 1987;8(6): 293-7.
- 20. Alves IL, Almeida MR, Skare J, Skinner M, Kurose K, Sakaki Y, Costa PP, Saraiva MJ. Amyloidogenic and non-amyloidogenic transthyretin Asn 90 variants. Clin Genet 1992;42(1):27-30.
- 21. Alves IL, Divino CM, Schussler GC, Altland K, Almeida MR, Palha JA, et al. Thyroxine binding in a TTR Met 119 kindred. J Clin Endocrinol Metab 1993; 77(2):484-8.
- 22. Haagsma EB, Hawkins PN, Benson MD, Lachmann HJ, Bybee A, Hazenberg BP. Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American- Finnish families. Amyloid 2004;11(1):44-9.
- 23. Bersano A, Del Bo R, Ballabio E, Cinnante C, Lanfranconi S, Comi GP, et al. Transthyretin Asn90 variant: amyloidogenic or nonamyloidogenic role. J Neurol Sci. 2009; 284(1- 2):113-5.
- 24. Solov’ev KV, Grudinina NA, Semernin EN, Morozova IV, Smirnova SA, Poliakov DS, Aleĭnikova TD, Shliakhto EV, Gudkova AY, Shavlovskiĭ MM. Transthyretin gene V30M, H90N, and del9 mutations in cardiomyopathy patients from St. Petersburg. Genetika. 2011;47(4):543-9.
Ayrıntılar
| Birincil Dil | Türkçe |
|---|---|
| Konular | Klinik Tıp Bilimleri |
| Bölüm | Research Article |
| Yazarlar | |
| Proje Numarası | 42173 ve TDP-2017-22581 |
| Yayımlanma Tarihi | 5 Kasım 2020 |
| Gönderilme Tarihi | 16 Eylül 2020 |
| Yayımlandığı Sayı | Yıl 2020 Cilt: 3 Sayı: 3 |
