Abstract
Summary
The Hajdu–Cheney syndrome is a very rare disease that affects several organ system, leading to severe osteoporosis and other abnormalities. We describe clinical and genetic findings of nine patients with this disease.
Introduction
The Hajdu–Cheney syndrome (HCS) is a rare autosomal dominant disorder characterized by severe osteoporosis, acroosteolysis of the distal phalanges, renal cysts, and other abnormalities. Recently, heterozygous mutations in NOTCH2 were identified as the cause of HCS.
Methods
Nine patients with typical presentations of HCS took part in this study: five affected patients from two small families and four sporadic cases. Peripheral blood DNA was obtained and exome sequencing performed in one affected individual per family and in all four sporadic cases. Sanger sequencing confirmed mutations in all patients.
Results
One of the identified mutations was introduced in a plasmid encoding NOTCH2. Wild-type and mutant NOTCH2 were transiently expressed in HEK293 cells to assess intracellular localization after ligand activation. Deleterious heterozygous mutations in the last NOTCH2 exon were identified in all patients; five of the six mutations were novel.
Conclusion
Consistent with previous reports, all mutations are predicted to result in a loss of the proline/glutamic acid/serine/threonine sequence, which harbors signals for degradation, therefore suggesting activating mutations. One of the six mutations furthermore predicted disruption of the second nuclear localization signal of NOTCH2, but the mutant revealed normal nuclear localization after transfection, which is consistent with the proposed gain-of-function mechanism as the cause of this autosomal dominant disease. Our findings confirm that heterozygous NOTCH2 mutations are the cause of HCS and expand the mutational spectrum of this disorder.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Hajdu N, Kauntze R (1948) Cranio-skeletal dysplasia. Br J Radiol 21:42–48
Cheney WD (1965) Acro-osteolysis. Am J Roentgenol Radium Ther Nucl Med 94:595–607
Brennan AM, Pauli RM (2001) Hajdu–Cheney syndrome: evolution of phenotype and clinical problems. Am J Med Genet 100:292–310
Isidor B, Lindenbaum P, Pichon O et al (2011) Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43:306–308
Simpson MA, Irving MD, Asilmaz E et al (2011) Mutations in NOTCH2 cause Hajdu–Cheney syndrome, a disorder of severe and progressive bone loss. Nat Genet 43:303–305
Schipani E, Weinstein LS, Bergwitz C et al (1995) Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene. J Clin Endocrinol Metab 80:1611–1621
Gnirke A, Melnikov A, Maguire J et al (2009) Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotechnol 27:182–189
DePristo MA, Banks E, Poplin R et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498
Cingolani P (2012) snpEff: variant effect prediction. http://snpeff.sourceforge.net
Zhao W, Hirose T, Ishikawa M, Oshima Y, Hirai S, Ohno S, Taniguchi H (2007) Neonatal pancreatic cells redifferentiate into both neural and pancreatic lineages. Biochem Biophys Res Commun 352:84–90
Crifasi PA, Patterson MC, Bonde D, Michels VV (1997) Severe Hajdu–Cheney syndrome with upper airway obstruction. Am J Med Genet 70:261–266
Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233
Penton A, Leonard L, Spinner N (2012) Notch signaling in human development and disease. Semin Cell Dev Biol 23(4):450–457
Maquat LE (2004) Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5:89–99
Rogers S, Wells R, Rechsteiner M (1986) Amino acid sequences common to rapidly degraded proteins: the PEST hypothesis. Science 234:364–368
Lee SY, Kumano K, Nakazaki K et al (2009) Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 100:920–926
Chiang MY, Xu ML, Histen G, Shestova O, Roy M, Nam Y, Blacklow SC, Sacks DB, Pear WS, Aster JC (2006) Identification of a conserved negative regulatory sequence that influences the leukemogenic activity of NOTCH1. Mol Cell Biol 26:6261–6271
Majewski J, Schwartzentruber JA, Caqueret A et al (2011) Mutations in NOTCH2 in families with Hajdu–Cheney syndrome. Hum Mutat 32:1114–1117
Jeffries S, Capobianco AJ (2000) Neoplastic transformation by Notch requires nuclear localization. Mol Cell Biol 20:3928–3941
Gray MJ, Kim CA, Bertola DR, Arantes PR, Stewart H, Simpson MA, Irving MD, Robertson SP (2012) Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu–Cheney syndrome. Eur J Hum Genet 20:122–124
Nunziata V, di Giovanni G, Ballanti P, Bonucci E (1990) High turnover osteoporosis in acro-osteolysis (Hajdu–Cheney syndrome). J Endocrinol Invest 13:251–255
Engin F, Yao Z, Yang T et al (2008) Dimorphic effects of Notch signaling in bone homeostasis. Nat Med 14:299–305
Canalis E, Parker K, Feng JQ, Zanotti S (2013) Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology 154(2):623–634
Fukushima H, Nakao A, Okamoto F, Shin M, Kajiya H, Sakano S, Bigas A, Jimi E, Okabe K (2008) The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis. Mol Cell Biol 28:6402–6412
Baldridge D, Shchelochkov O, Kelley B, Lee B (2010) Signaling pathways in human skeletal dysplasias. Annu Rev Genomics Hum Genet 11:189–217
Acknowledgments
We like to thank all patients and family members who participated in this study. We thank the Broad Institute for generating high-quality sequence data supported by NHGRI funds (U54 HG003067, PI Eric Lander), Harald Jüppner for support and Spyros Artavanis-Tsakonas for the Notch2 cDNA plasmid. This research was supported, in part, by grants from the National Institute of Diabetes and Digestive and Kidney Disease (K08-DK081669-01 to M.M.) and by the Division of Intramural Research, NIDCR, a part of the Intramural Research Program of the NIH, DHHS.
Conflicts of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zhao, W., Petit, E., Gafni, R.I. et al. Mutations in NOTCH2 in patients with Hajdu–Cheney syndrome. Osteoporos Int 24, 2275–2281 (2013). https://doi.org/10.1007/s00198-013-2298-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00198-013-2298-5