E-ISSN: 1308-5263
A Novel ATP6V0A2 Mutation Causing Recessive Cutis Laxa with Unusual Manifestations of Bleeding Diathesis and Defective Wound Healing [Turk J Hematol]
Turk J Hematol. 2019; 36(1): 29-36 | DOI: 10.4274/tjh.galenos.2018.2018.0325  

A Novel ATP6V0A2 Mutation Causing Recessive Cutis Laxa with Unusual Manifestations of Bleeding Diathesis and Defective Wound Healing

İlker Karacan1, Reyhan Diz Küçükkaya2, Fatma Nur Karakuş3, Seyhun Solakoğlu3, Aslıhan Tolun4, Veysel Sabri Hancer5, Eda Tahir Turanlı6
1İstanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, İstanbul, Turkey; İstanbul Medeniyet University, Department of Molecular Biology and Genetics, İstanbul, Turkey
2İstanbul Bilim University, Faculty of Medicine, Department of Hematology, İstanbul, Turkey
3İstanbul University, İstanbul Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
4Boğaziçi University, Department of Molecular Biology and Genetics, İstanbul, Turkey
5İstanbul Bilim University, Department of Molecular Biology and Genetics, İstanbul, Turkey
6İstanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, İstanbul, Turkey; İstanbul Technical University, Department of Molecular Biology and Genetics, İstanbul, Turkey

Objective: Autosomal recessive cutis laxa type IIA (ARCL2A) is a rare congenital disorder characterized by loose and elastic skin, growth and developmental delay, and skeletal anomalies. It is caused by biallelic mutations in ATP6V0A2. Those mutations lead to increased pH in secretory vesicles and thereby to impaired glycosyltransferase activity and organelle trafficking. We aimed to identify the genetic and molecular cause of the unexpected hematological findings in a Turkish family.
Materials and Methods: We performed clinical, genetic, and histological analyses of a consanguineous family afflicted with wrinkled and loose skin, microcephaly, intellectual disability, cleft lip and palate, downslanting palpebral fissures, ectopia lentis, bleeding diathesis, and defective wound healing.
Results: Linkage analysis using SNP genotype data yielded a maximal multipoint logarithm of odds score of 2.59 at 12q24.21-24.32. Exome sequence analysis for the proband led to the identification of novel homozygous frameshift c.2085_2088del (p.(Ser695Argfs*12)) in ATP6V0A2, within the linked region, in the two affected siblings.
Conclusion: Our patients do not have gross structural brain defects besides microcephaly, strabismus, myopia, and growth or developmental delay. Large platelets were observed in the patients and unusual electron-dense intracytoplasmic inclusions in fibroblasts and epidermal basal cells were observed in both affected and unaffected family members. The patients do not have any genetic defect in the VWF gene but von Willebrand factor activity to antigen ratios were low. Clinical findings of bleeding diathesis and defective wound healing have not been reported in ARCL2A and hence our findings expand the phenotypic spectrum of the disease.

Keywords: ATP6V0A2, Cutis laxa, Wound healing, Bleeding diathesis, Whole exome sequencing


Alışılmadık Kanama Eğilimi ve Yetersiz Yara İyileşmesi Bulgularıyla Görülen Çekinik Kutis Laksaya Sebep Olan Yeni Bir ATP6V0A2 Mutasyonu

İlker Karacan1, Reyhan Diz Küçükkaya2, Fatma Nur Karakuş3, Seyhun Solakoğlu3, Aslıhan Tolun4, Veysel Sabri Hancer5, Eda Tahir Turanlı6
1İstanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, İstanbul, Turkey; İstanbul Medeniyet University, Department of Molecular Biology and Genetics, İstanbul, Turkey
2İstanbul Bilim University, Faculty of Medicine, Department of Hematology, İstanbul, Turkey
3İstanbul University, İstanbul Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
4Boğaziçi University, Department of Molecular Biology and Genetics, İstanbul, Turkey
5İstanbul Bilim University, Department of Molecular Biology and Genetics, İstanbul, Turkey
6İstanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, İstanbul, Turkey; İstanbul Technical University, Department of Molecular Biology and Genetics, İstanbul, Turkey

Amaç: Otozomal çekinik kutis laksa tip IIA (ARCL2A) nadir görülen ve doğuştan bir hastalık olup, gevşek ve elastik deri, büyüme ve gelişme geriliği, iskelet anomalileri ile karakterizedir. ATP6V0A2 genindeki biallelik mutasyonlar hastalığa sebep olmaktadır. Bu mutasyonlar salgı veziküllerinde pH artışına yol açtığından, glikoziltransferaz aktivitesi ve organel trafiği bozulur. Bu çalışmada beklenmedik hematolojik bulguları da olan Türk ailede hastalığın genetik ve moleküler sebeplerinin bulunması amaçlanmıştır.
Gereç ve Yöntem: Akraba ebeveynin iki çocuğunda buruşuk ve gevşek deri, mikrosefali, zihinsel yetersizlik, yarık dudak ve damak, aşağı eğimli palpebral fissür, mercek dislokasyonu, kanama eğilimi ve yetersiz yara iyileşmesi bulguları görüldü ve klinik, genetik ve histolojik analizler gerçekleştirildi.
Bulgular: SNP genotip verisi kullanılarak yapılan bağlantı analizi sonucunda 12q24.21-24.32 kromozomal bölgesinde en yüksek çok noktalı LOD skor olan 2,59 elde edilmiştir. Bu bölgede indeks hastanın ekzom verilerinde, her iki hastada da homozigot durumda olan ve daha önce bildirilmemiş ATP6V0A2 geninde çerçeve kaymasına yol açan c.2085_2088del (p.(Ser695Argfs*12)) varyantı tespit edildi.
Sonuç: Hastalarda mikrosefali dışında yapısal beyin bozukluğu, şaşılık, miyop, büyüme veya gelişme geriliği yoktur. Yalnızca hastalarda büyük hacimli trombositler, hem hasta hem de sağlıklı bireylerde ise fibroblast ve epidermal bazal hücrelerde alışılmadık elektron-yoğun intrasitoplazmik inklüzyonlar görülmüştür. Hastalarda VWF gen bozukluğu görülmemiş olup, von Willebrand faktörü aktivite/antijen oranı düşüktür. Kanama eğilimi ve yetersiz yara iyileşmesi daha önce ARCL2A hastalığında rapor edilmemiş olup, bulgularımız hastalığın fenotipik spektrumunu genişletmektedir.

Anahtar Kelimeler: ATP6V0A2, Kutis laksa, Yara iyileşmesi, Kanama diyatezi, Tüm ekzom dizi analizi


İlker Karacan, Reyhan Diz Küçükkaya, Fatma Nur Karakuş, Seyhun Solakoğlu, Aslıhan Tolun, Veysel Sabri Hancer, Eda Tahir Turanlı. A Novel ATP6V0A2 Mutation Causing Recessive Cutis Laxa with Unusual Manifestations of Bleeding Diathesis and Defective Wound Healing. Turk J Hematol. 2019; 36(1): 29-36

Corresponding Author: Eda Tahir Turanlı, Türkiye


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