Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis


  1. Sobacchi C, Schulz A, Coxon FP, Villa A, Helfrich MH.
    Osteopetrosis: genetics, treatment and new insights into osteoclast function.
    Nat Rev Endocrinol. 2013; 9:522–536.
  2. Sobacchi C, Pangrazio A, López AG, et al.
    As little as needed: the extraordinary case of a mild recessive osteopetrosis due to a novel splicing hypomorphic mutation in the TCIRG1 gene.
    J Bone Miner Res. 2014; 29:1646–1650.
  3. Rabbani B, Tekin M, Mahdieh N.
    The promise of whole-exome sequencing in medical genetics.
    J Hum Genet. 2014; 59:5–15.
  4. Li H, Durbin R.
    Fast and accurate long-read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2010; 26:589–595.
  5. McKenna A, Hanna M, Banks E, et al.
    The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data.
    Genome Res. 2010; 20:1297–303.
  6. Cuccuru G, Orsini M, Pinna A, et al.
    Orione, a web-based framework for NGS analysis in microbiology.
    Bioinformatics. 2014; 30:1928–1929.
  7. Li M-X., Kwan JSH, Bao S-Y, et al.
    Predicting Mendelian disease-causing non-synonymous single nucleotide variants in exome sequencing studies.
    PLoS Genet. 2013; 9:e1003143.
  8. Frattini A, Orchard PJ, Sobacchi C, et al.
    Defects in the TCIRG1-encoded 116kD subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis.
    Nat Genet. 2000; 25:343–346.
  9. Frattini A, Pangrazio A, Susani L, et al.
    Chloride channel ClCN7 mutations are responsible for severe recessive, dominant and intermediate osteopetrosis.
    J Bone Miner Res. 2003; 18:1740–1747.
  10. Van Wesenbeeck L, Odgren PR, Coxon FP, et al.
    Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans.
    J Clin Invest. 2007; 117:919–930.
  11. Sobacchi C, Frattini A, Guerrini M, et al.
    Osteoclast-poor human osteopetrosis due to mutations in RANKL.
    Nat Genet. 2007; 39:960–962.
  12. Guerrini MM, Sobacchi C, Cassani B, et al.
    Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.
    Am J Hum Genet. 2008; 83:64–76.
  13. Pangrazio A, Fasth A, Sbardellati A, et al.
    SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.
    J Bone Miner Res. 2013; 28:1041–1049.
  14. Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C.
    Human Splicing Finder: an online bioinformatics tool to predict splicing signals.
    Nucl Acids Res. 2009; 37:e67.
  15. Den Dunnen JT, Antonarakis SE.
    Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.
    Hum Mutat. 2000; 15:7–12.
  16. Robinson LJ, Mancarella S, Songsawad D, et al.
    Gene disruption of the calcium channel Orai1 results in inhibition of osteoclast and osteoblast differentiation and impairs skeletal development.
    Lab Invest. 2012; 92:1071–1083.
  17. Mazzolari E, Forino C, Razza A, Porta F, Villa A, Notarangelo LD.
    A single-center experience in 20 patients with infantile malignant osteopetrosis.
    Am J Hematol. 2009; 84:473–479.
  18. Balemans W, Van Hul W.
    The genetics of low-density lipoprotein receptor-related protein 5 in bone: a story of extremes.
    Endocrinology. 2007; 148:2622–2629.
  19. Zeng X, Tamai K, Doble B, et al.
    A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation.
    Nature. 2005; 438:873–877.
  20. Katoh M, Katoh M.
    WNT signaling pathway and stem cell signaling network.
    Clin Cancer Res. 2007; 13:4042–4045.
  21. Michalova E, Vojtesek B, Hrstka R.
    Impaired pre-mRNA processing and altered architecture of 3′ untranslated regions contribute to the development of human disorders.
    Int J Mol Sci. 2013; 14:15681–15694.
  22. Sobacchi C, Frattini A, Orchard P, et al.
    The mutational spectrum of human malignant autosomal recessive osteopetrosis.
    Hum Mol Genet. 2001; 10:1767–1773.
  23. Bax NM, Sangermano R, Roosing S, et al.
    Heterozygous deep-intronic variants and deletions in ABCA4 in persons with retinal dystrophies and one exonic ABCA4 variant.
    Hum Mutat. 2015; 36:43–47.
  24. Bholah Z, Smith MJ, Byers HJ, Miles EK, Evans DG, Newman WG.
    Intronic splicing mutations in PTCH1 cause Gorlin syndrome.
    Fam Cancer. 2014; 13:477–480.
  25. Bonifert T, Karle KN, Tonagel F, et al.
    Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier.
    Brain. 2014; 137:2164–2177.
  26. Gillis E, Kempers M, Salemink S, et al.
    An FBN1 deep intronic mutation in a familial case of Marfan syndrome: an explanation for genetically unsolved cases?
    Hum Mutat. 2014; 35:571–574.
  27. Zeevaert R, de Zegher F, Sturiale L, et al.
    Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165.
    JIMD Rep. 2013; 8:145–152.
  28. Pettersson U, Albagha OME, Mirolo M, et al.
    Polymorphisms of the CLCN7 gene are associated with BMD in women.
    J Bone Miner Res. 2005; 20:1960–1967.
  29. Chu K, Snyder R, Econs MJ.
    Disease status in autosomal dominant osteopetrosis type 2 is determined by osteoclastic properties.
    J Bone Miner Res. 2006; 21:1089–1097.
  30. Gong Y, Slee RB, Fukai N, et al.
    LDL receptor related protein 5 (LRP5) affects bone accrual and eye development.
    Cell. 2001; 107:513–523.
  31. Balemans W, Devogelaer JP, Cleiren E, Piters E, Caussin E, Van Hul W.
    Novel LRP5 missense mutation in a patient with a high bone mass phenotype results in decreased DKK1-mediated inhibition of Wnt signaling.
    J Bone Miner Res. 2007; 22:708–716.