Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy

Paulina Navon Elkan, Sarah B. Pierce, Reeval Segel, Tom Walsh, Judith Barash, Shai Padeh, Abraham Zlotogorski, Yackov Berkun, Joseph J. Press, Masha Mukamel, Isabel Voth, Philip J. Hashkes, Liora Harel, Vered Hoffer, Eduard Ling, Fatos Yalcinkaya, Ozgur Kasapcopur, Ming K. Lee, Rachel E. Klevit, Paul RenbaumAriella Weinberg-Shukron, Elif F. Sener, Barbara Schormair, Sharon Zeligson, Dina Marek-Yagel, Tim M. Strom, Mordechai Shohat, Amihood Singer, Alan Rubinow, Elon Pras, Juliane Winkelmann, Mustafa Tekin, Yair Anikster, Mary Claire King, Ephrat Levy-Lahad

Research output: Contribution to journalArticle

247 Citations (Scopus)

Abstract

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression.

Original languageEnglish
Pages (from-to)921-931
Number of pages11
JournalNew England Journal of Medicine
Volume370
Issue number10
DOIs
StatePublished - Jan 1 2014

Fingerprint

Polyarteritis Nodosa
Adenosine Deaminase
Mutation
Exome
Systemic Vasculitis
HEK293 Cells
Mutant Proteins
Vasculitis
Serum
Intercellular Signaling Peptides and Proteins
Proteins
Kidney
Skin
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Elkan, P. N., Pierce, S. B., Segel, R., Walsh, T., Barash, J., Padeh, S., ... Levy-Lahad, E. (2014). Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. New England Journal of Medicine, 370(10), 921-931. https://doi.org/10.1056/NEJMoa1307362

Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. / Elkan, Paulina Navon; Pierce, Sarah B.; Segel, Reeval; Walsh, Tom; Barash, Judith; Padeh, Shai; Zlotogorski, Abraham; Berkun, Yackov; Press, Joseph J.; Mukamel, Masha; Voth, Isabel; Hashkes, Philip J.; Harel, Liora; Hoffer, Vered; Ling, Eduard; Yalcinkaya, Fatos; Kasapcopur, Ozgur; Lee, Ming K.; Klevit, Rachel E.; Renbaum, Paul; Weinberg-Shukron, Ariella; Sener, Elif F.; Schormair, Barbara; Zeligson, Sharon; Marek-Yagel, Dina; Strom, Tim M.; Shohat, Mordechai; Singer, Amihood; Rubinow, Alan; Pras, Elon; Winkelmann, Juliane; Tekin, Mustafa; Anikster, Yair; King, Mary Claire; Levy-Lahad, Ephrat.

In: New England Journal of Medicine, Vol. 370, No. 10, 01.01.2014, p. 921-931.

Research output: Contribution to journalArticle

Elkan, PN, Pierce, SB, Segel, R, Walsh, T, Barash, J, Padeh, S, Zlotogorski, A, Berkun, Y, Press, JJ, Mukamel, M, Voth, I, Hashkes, PJ, Harel, L, Hoffer, V, Ling, E, Yalcinkaya, F, Kasapcopur, O, Lee, MK, Klevit, RE, Renbaum, P, Weinberg-Shukron, A, Sener, EF, Schormair, B, Zeligson, S, Marek-Yagel, D, Strom, TM, Shohat, M, Singer, A, Rubinow, A, Pras, E, Winkelmann, J, Tekin, M, Anikster, Y, King, MC & Levy-Lahad, E 2014, 'Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy', New England Journal of Medicine, vol. 370, no. 10, pp. 921-931. https://doi.org/10.1056/NEJMoa1307362
Elkan PN, Pierce SB, Segel R, Walsh T, Barash J, Padeh S et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. New England Journal of Medicine. 2014 Jan 1;370(10):921-931. https://doi.org/10.1056/NEJMoa1307362
Elkan, Paulina Navon ; Pierce, Sarah B. ; Segel, Reeval ; Walsh, Tom ; Barash, Judith ; Padeh, Shai ; Zlotogorski, Abraham ; Berkun, Yackov ; Press, Joseph J. ; Mukamel, Masha ; Voth, Isabel ; Hashkes, Philip J. ; Harel, Liora ; Hoffer, Vered ; Ling, Eduard ; Yalcinkaya, Fatos ; Kasapcopur, Ozgur ; Lee, Ming K. ; Klevit, Rachel E. ; Renbaum, Paul ; Weinberg-Shukron, Ariella ; Sener, Elif F. ; Schormair, Barbara ; Zeligson, Sharon ; Marek-Yagel, Dina ; Strom, Tim M. ; Shohat, Mordechai ; Singer, Amihood ; Rubinow, Alan ; Pras, Elon ; Winkelmann, Juliane ; Tekin, Mustafa ; Anikster, Yair ; King, Mary Claire ; Levy-Lahad, Ephrat. / Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. In: New England Journal of Medicine. 2014 ; Vol. 370, No. 10. pp. 921-931.
@article{38fdf2550c9249a29fa93db83eff7789,
title = "Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy",
abstract = "BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression.",
author = "Elkan, {Paulina Navon} and Pierce, {Sarah B.} and Reeval Segel and Tom Walsh and Judith Barash and Shai Padeh and Abraham Zlotogorski and Yackov Berkun and Press, {Joseph J.} and Masha Mukamel and Isabel Voth and Hashkes, {Philip J.} and Liora Harel and Vered Hoffer and Eduard Ling and Fatos Yalcinkaya and Ozgur Kasapcopur and Lee, {Ming K.} and Klevit, {Rachel E.} and Paul Renbaum and Ariella Weinberg-Shukron and Sener, {Elif F.} and Barbara Schormair and Sharon Zeligson and Dina Marek-Yagel and Strom, {Tim M.} and Mordechai Shohat and Amihood Singer and Alan Rubinow and Elon Pras and Juliane Winkelmann and Mustafa Tekin and Yair Anikster and King, {Mary Claire} and Ephrat Levy-Lahad",
year = "2014",
month = "1",
day = "1",
doi = "10.1056/NEJMoa1307362",
language = "English",
volume = "370",
pages = "921--931",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "10",

}

TY - JOUR

T1 - Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy

AU - Elkan, Paulina Navon

AU - Pierce, Sarah B.

AU - Segel, Reeval

AU - Walsh, Tom

AU - Barash, Judith

AU - Padeh, Shai

AU - Zlotogorski, Abraham

AU - Berkun, Yackov

AU - Press, Joseph J.

AU - Mukamel, Masha

AU - Voth, Isabel

AU - Hashkes, Philip J.

AU - Harel, Liora

AU - Hoffer, Vered

AU - Ling, Eduard

AU - Yalcinkaya, Fatos

AU - Kasapcopur, Ozgur

AU - Lee, Ming K.

AU - Klevit, Rachel E.

AU - Renbaum, Paul

AU - Weinberg-Shukron, Ariella

AU - Sener, Elif F.

AU - Schormair, Barbara

AU - Zeligson, Sharon

AU - Marek-Yagel, Dina

AU - Strom, Tim M.

AU - Shohat, Mordechai

AU - Singer, Amihood

AU - Rubinow, Alan

AU - Pras, Elon

AU - Winkelmann, Juliane

AU - Tekin, Mustafa

AU - Anikster, Yair

AU - King, Mary Claire

AU - Levy-Lahad, Ephrat

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression.

AB - BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression.

UR - http://www.scopus.com/inward/record.url?scp=84895465707&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895465707&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1307362

DO - 10.1056/NEJMoa1307362

M3 - Article

C2 - 24552285

AN - SCOPUS:84895465707

VL - 370

SP - 921

EP - 931

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 10

ER -