Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations

Matteo M. Guerrini, Cristina Sobacchi, Barbara Cassani, Mario Abinun, Sara S. Kilic, Alessandra Pangrazio, Daniele Moratto, Evelina Mazzolari, Jill Clayton-Smith, Paul Orchard, Fraser Coxon, Miep H. Helfrich, Julie C. Crockett, David Mellis, Ashok Vellodi, Ilhan Tezcan, Luigi D. Notarangelo, Michael J. Rogers, Paolo Vezzoni, Anna VillaAnnalisa Frattini

Research output: Contribution to journalArticle

188 Citations (Scopus)

Abstract

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.
Original languageEnglish
Pages (from-to)64-76
Number of pages13
JournalAmerican Journal of Human Genetics
Volume83
Issue number1
DOIs
Publication statusPublished - 11 Jul 2008

Keywords

  • acid phosphatase
  • actins
  • agammaglobulinemia
  • amino acid sequence
  • amino acid substitution
  • antigens, CD45
  • Argentina
  • arginine
  • biopsy
  • case-control studies
  • cell line, transformed
  • cell proliferation
  • cell transformation, viral
  • cells, cultured
  • cohort studies
  • consanguinity
  • cysteine
  • DNA mutational analysis
  • dendrites
  • female
  • genes, recessive
  • herpesvirus 4, human
  • heterozygote
  • homozygote
  • humans
  • ilium
  • isoenzymes
  • leukocytes, mononuclear
  • lipopolysaccharides
  • macrophage colony-stimulating factor
  • male
  • models, immunological
  • molecular sequence data
  • mutation, missense
  • osteoclasts
  • osteopetrosis
  • osteoprotegerin
  • Pakistan
  • pedigree
  • Polymorphism, Genetic
  • Protein Structure, Tertiary
  • RANK Ligand
  • radiography, thoracic
  • receptor activator of nuclear factor-kappa B
  • receptors, vitronectin
  • sequence homology, amino acid
  • Turkey

Cite this

Guerrini, M. M., Sobacchi, C., Cassani, B., Abinun, M., Kilic, S. S., Pangrazio, A., ... Frattini, A. (2008). Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. American Journal of Human Genetics, 83(1), 64-76. https://doi.org/10.1016/j.ajhg.2008.06.015

Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. / Guerrini, Matteo M.; Sobacchi, Cristina; Cassani, Barbara; Abinun, Mario; Kilic, Sara S.; Pangrazio, Alessandra; Moratto, Daniele; Mazzolari, Evelina; Clayton-Smith, Jill; Orchard, Paul; Coxon, Fraser; Helfrich, Miep H.; Crockett, Julie C.; Mellis, David; Vellodi, Ashok; Tezcan, Ilhan; Notarangelo, Luigi D.; Rogers, Michael J.; Vezzoni, Paolo; Villa, Anna; Frattini, Annalisa.

In: American Journal of Human Genetics, Vol. 83, No. 1, 11.07.2008, p. 64-76.

Research output: Contribution to journalArticle

Guerrini, MM, Sobacchi, C, Cassani, B, Abinun, M, Kilic, SS, Pangrazio, A, Moratto, D, Mazzolari, E, Clayton-Smith, J, Orchard, P, Coxon, F, Helfrich, MH, Crockett, JC, Mellis, D, Vellodi, A, Tezcan, I, Notarangelo, LD, Rogers, MJ, Vezzoni, P, Villa, A & Frattini, A 2008, 'Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations', American Journal of Human Genetics, vol. 83, no. 1, pp. 64-76. https://doi.org/10.1016/j.ajhg.2008.06.015
Guerrini, Matteo M. ; Sobacchi, Cristina ; Cassani, Barbara ; Abinun, Mario ; Kilic, Sara S. ; Pangrazio, Alessandra ; Moratto, Daniele ; Mazzolari, Evelina ; Clayton-Smith, Jill ; Orchard, Paul ; Coxon, Fraser ; Helfrich, Miep H. ; Crockett, Julie C. ; Mellis, David ; Vellodi, Ashok ; Tezcan, Ilhan ; Notarangelo, Luigi D. ; Rogers, Michael J. ; Vezzoni, Paolo ; Villa, Anna ; Frattini, Annalisa. / Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. In: American Journal of Human Genetics. 2008 ; Vol. 83, No. 1. pp. 64-76.
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abstract = "Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.",
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T1 - Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations

AU - Guerrini, Matteo M.

AU - Sobacchi, Cristina

AU - Cassani, Barbara

AU - Abinun, Mario

AU - Kilic, Sara S.

AU - Pangrazio, Alessandra

AU - Moratto, Daniele

AU - Mazzolari, Evelina

AU - Clayton-Smith, Jill

AU - Orchard, Paul

AU - Coxon, Fraser

AU - Helfrich, Miep H.

AU - Crockett, Julie C.

AU - Mellis, David

AU - Vellodi, Ashok

AU - Tezcan, Ilhan

AU - Notarangelo, Luigi D.

AU - Rogers, Michael J.

AU - Vezzoni, Paolo

AU - Villa, Anna

AU - Frattini, Annalisa

PY - 2008/7/11

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N2 - Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.

AB - Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.

KW - acid phosphatase

KW - actins

KW - agammaglobulinemia

KW - amino acid sequence

KW - amino acid substitution

KW - antigens, CD45

KW - Argentina

KW - arginine

KW - biopsy

KW - case-control studies

KW - cell line, transformed

KW - cell proliferation

KW - cell transformation, viral

KW - cells, cultured

KW - cohort studies

KW - consanguinity

KW - cysteine

KW - DNA mutational analysis

KW - dendrites

KW - female

KW - genes, recessive

KW - herpesvirus 4, human

KW - heterozygote

KW - homozygote

KW - humans

KW - ilium

KW - isoenzymes

KW - leukocytes, mononuclear

KW - lipopolysaccharides

KW - macrophage colony-stimulating factor

KW - male

KW - models, immunological

KW - molecular sequence data

KW - mutation, missense

KW - osteoclasts

KW - osteopetrosis

KW - osteoprotegerin

KW - Pakistan

KW - pedigree

KW - Polymorphism, Genetic

KW - Protein Structure, Tertiary

KW - RANK Ligand

KW - radiography, thoracic

KW - receptor activator of nuclear factor-kappa B

KW - receptors, vitronectin

KW - sequence homology, amino acid

KW - Turkey

U2 - 10.1016/j.ajhg.2008.06.015

DO - 10.1016/j.ajhg.2008.06.015

M3 - Article

C2 - 18606301

VL - 83

SP - 64

EP - 76

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 1

ER -