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

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

�lker Karacan¹, Reyhan Diz K��kkaya², Fatma Nur Karaku�³, Seyhun Solako�lu³, Asl�han Tolun⁴, Veysel Sabri Hancer⁵, Eda Tahir Turanl�⁶
¹�stanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, �stanbul, Turkey; �stanbul Medeniyet University, Department of Molecular Biology and Genetics, �stanbul, Turkey
²�stanbul Bilim University, Faculty of Medicine, Department of Hematology, �stanbul, Turkey
³�stanbul University, �stanbul Faculty of Medicine, Department of Histology and Embryology, �stanbul, Turkey
⁴Bo�azi�i University, Department of Molecular Biology and Genetics, �stanbul, Turkey
⁵�stanbul Bilim University, Department of Molecular Biology and Genetics, �stanbul, Turkey
⁶�stanbul Technical University, Graduate School of Science, Engineering and Technology, Department of Molecular Biology-Genetics and Biotechnology, �stanbul, Turkey; �stanbul Technical University, Department of Molecular Biology and Genetics, �stanbul, 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

Al��lmad�k Kanama E�ilimi ve Yetersiz Yara �yile�mesi Bulgular�yla G�r�len �ekinik Kutis Laksaya Sebep Olan Yeni Bir ATP6V0A2 Mutasyonu

Ama�: Otozomal �ekinik kutis laksa tip IIA (ARCL2A) nadir g�r�len ve do�u�tan bir hastal�k olup, gev�ek ve elastik deri, b�y�me ve geli�me gerili�i, iskelet anomalileri ile karakterizedir. ATP6V0A2 genindeki biallelik mutasyonlar hastal��a sebep olmaktad�r. Bu mutasyonlar salg� vezik�llerinde pH art��na yol a�t��ndan, glikoziltransferaz aktivitesi ve organel trafi�i bozulur. Bu �al��mada beklenmedik hematolojik bulgular� da olan T�rk ailede hastal��n genetik ve molek�ler sebeplerinin bulunmas� ama�lanm��t�r.
Gere� ve Y�ntem: Akraba ebeveynin iki �ocu�unda buru�uk ve gev�ek deri, mikrosefali, zihinsel yetersizlik, yar�k dudak ve damak, a�a�� e�imli palpebral fiss�r, mercek dislokasyonu, kanama e�ilimi ve yetersiz yara iyile�mesi bulgular� g�r�ld� ve klinik, genetik ve histolojik analizler ger�ekle�tirildi.
Bulgular: SNP genotip verisi kullan�larak yap�lan ba�lant� analizi sonucunda 12q24.21-24.32 kromozomal b�lgesinde en y�ksek �ok noktal� LOD skor olan 2,59 elde edilmi�tir. Bu b�lgede indeks hastan�n ekzom verilerinde, her iki hastada da homozigot durumda olan ve daha �nce bildirilmemi� ATP6V0A2 geninde �er�eve kaymas�na yol a�an c.2085_2088del (p.(Ser695Argfs*12)) varyant� tespit edildi.
Sonu�: Hastalarda mikrosefali d��nda yap�sal beyin bozuklu�u, �a��l�k, miyop, b�y�me veya geli�me gerili�i yoktur. Yaln�zca hastalarda b�y�k hacimli trombositler, hem hasta hem de sa�l�kl� bireylerde ise fibroblast ve epidermal bazal h�crelerde al��lmad�k elektron-yo�un intrasitoplazmik inkl�zyonlar g�r�lm��t�r. Hastalarda VWF gen bozuklu�u g�r�lmemi� olup, von Willebrand fakt�r� aktivite/antijen oran� d��kt�r. Kanama e�ilimi ve yetersiz yara iyile�mesi daha �nce ARCL2A hastal��nda rapor edilmemi� olup, bulgular�m�z hastal��n fenotipik spektrumunu geni�letmektedir.

Anahtar Kelimeler: ATP6V0A2, Kutis laksa, Yara iyile�mesi, Kanama diyatezi, T�m ekzom dizi analizi

�lker Karacan, Reyhan Diz K��kkaya, Fatma Nur Karaku�, Seyhun Solako�lu, Asl�han Tolun, Veysel Sabri Hancer, Eda Tahir Turanl�. 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 Turanl�, T�rkiye

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

Al���lmad�k Kanama E�ilimi ve Yetersiz Yara �yile�mesi Bulgular�yla G�r�len �ekinik Kutis Laksaya Sebep Olan Yeni Bir ATP6V0A2 Mutasyonu

Al��lmad�k Kanama E�ilimi ve Yetersiz Yara �yile�mesi Bulgular�yla G�r�len �ekinik Kutis Laksaya Sebep Olan Yeni Bir ATP6V0A2 Mutasyonu