Mutations in ATP6V1E1 or ATP6V1A Cause Autosomal-Recessive Cutis Laxa

被引：79

作者：

Van Damme, Tim ^{[1
,2
]}

Gardeitchik, Thatjana ^{[3
,4
]}

Mohamed, Miski ^{[3
]}

Guerrero-Castillo, Sergio ^{[5
,6
]}

Freisinger, Peter ^{[7
]}

Guillemyn, Brecht ^{[1
,2
]}

Kariminejad, Ariana ^{[8
]}

Dalloyaux, Daisy ^{[3
,6
]}

Van Kraaij, Sanne ^{[3
,6
]}

Lefeber, Dirk J. ^{[6
,9
]}

Syx, Delfien ^{[1
,2
]}

Steyaert, Wouter ^{[1
,2
]}

De Rycke, Riet ^{[10
,11
]}

Hoischen, Alexander ^{[4
]}

Kamsteeg, Erik-Jan ^{[4
]}

Wong, Sunnie Y. ^{[12
]}

van Scherpenzeel, Monique ^{[6
,9
]}

Jamali, Payman ^{[13
]}

Brandt, Ulrich ^{[5
,6
]}

Nijtmans, Leo ^{[5
,6
]}

Korenke, G. Christoph ^{[14
]}

Chung, Brian H. Y. ^{[15
]}

Mak, Christopher C. Y. ^{[15
]}

Hausser, Ingrid ^{[16
]}

Kornak, Uwe ^{[17
,18
]}

Fischer-Zirnsak, Bjorn ^{[17
,18
]}

Strom, Tim M. ^{[19
]}

Meitinger, Thomas ^{[19
]}

Alanay, Yasemin ^{[20
]}

Utine, Gulen E. ^{[21
]}

Leung, Peter K. C. ^{[15
]}

Ghaderi-Sohi, Siavash ^{[8
]}

Coucke, Paul ^{[1
,2
]}

Symoens, Sofie ^{[1
,2
]}

De Paepe, Anne ^{[1
,2
]}

Thiel, Christian ^{[22
]}

Haack, Tobias B. ^{[19
,23
,24
]}

Malfait, Fransiska ^{[1
,2
]}

Morava, Eva ^{[12
,25
]}

Callewaert, Bert ^{[1
,2
]}

Wevers, Ron A. ^{[6
]}

机构：

[1] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium

[2] Ghent Univ Hosp, B-9000 Ghent, Belgium

[3] Radboud Univ Nijmegen, Med Ctr, Dept Pediat, NL-6500 HB Nijmegen, Netherlands

[4] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Radboud Ctr Mitochondrial Med, Dept Pediat, NL-6500 HB Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Translat Metab Lab, Dept Lab Med, NL-6500 HB Nijmegen, Netherlands

[7] Klinikum Steinenberg, Childrens Hosp, D-72764 Reutlingen, Germany

[8] Kariminejad Najmabadi Pathol & Genet Ctr, Tehran 14656, Iran

[9] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6500 HB Nijmegen, Netherlands

[10] Univ Ghent, Dept Biomed Mol Biol, B-9000 Ghent, Belgium

[11] VIB, Inflammat Res Ctr, B-9000 Ghent, Belgium

[12] Tulane Univ, Sch Med, Hayward Genet Ctr, 1430 Tulane Ave, New Orleans, LA 70112 USA

[13] Shahrood Genet Counseling Ctr, Semnan 36156, Iran

[14] Childrens Hosp Klinikum Oldenburg, Dept Neuropediat, D-26133 Oldenburg, Germany

[15] Univ Hong Kong, Dept Paediat & Adolescent Med, Li Ka Shing Fac Med, Hong Kong, Hong Kong, Peoples R China

[16] Univ Klinikum Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany

[17] Charite, Inst Med Genet & Human Genet, D-13353 Berlin, Germany

[18] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[19] Helmholtz Zentrum Munchen, Inst Human Genet, D-85764 Neuherberg, Germany

[20] Acibadem Univ, Sch Med, Pediat Genet Unit, Dept Pediat, TR-34752 Istanbul, Turkey

[21] Ihsan Dogramaci Childrens Hosp, Pediat Genet Unit, Dept Pediat, Hacettepe Sch Med, TR-06100 Ankara, Turkey

[22] Univ Klinikum Heidelberg, Ctr Child & Adolescent Med, Klin Kinderheilkunde 1, D-69120 Heidelberg, Germany

[23] Tech Univ Munich, Inst Human Genet, D-81675 Munich, Germany

[24] Univ Tubingen, Inst Med Genet & Appl Genom, D-72076 Tubingen, Germany

[25] Univ Hosp Leuven, Dept Pediat, B-3000 Leuven, Belgium

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 100卷 / 02期

关键词：

RENAL TUBULAR-ACIDOSIS; VACUOLAR PROTON PUMP; CONGENITAL DISORDERS; GOLGI HOMEOSTASIS; DEFICIENCY CAUSES; ATPASE; SUBUNIT; PLATFORM; IMAGE; IDENTIFICATION;

D O I：

10.1016/j.ajhg.2016.12.010

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Defects of the V-type proton (H+) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the El and A subunits, respectively, of the V-1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions. Furthermore, complexome profiling, a method combining blue-native gel electrophoresis and liquid chromatography tandem mass spectrometry, showed that they disturb either the assembly or the stability of the V-ATPase complex. Protein glycosylation was variably affected. Abnormal vesicular trafficking was evidenced by delayed retrograde transport after brefeldin A treatment and abnormal swelling and fragmentation of the Golgi apparatus. In addition to showing reduced and fragmented elastic fibers, the histopathological hallmark of cutis laxa, transmission electron microscopy of the dermis also showed pronounced changes in the structure and organization of the collagen fibers. Our findings expand the clinical and molecular spectrum of metabolic cutis laxa syndromes and further link defective extracellular matrix assembly to faulty protein processing and cellular trafficking caused by genetic defects in the V-ATPase complex.

引用

页码：216 / 227

页数：12

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