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Bone. 2014 Nov;68:142-5. doi: 10.1016/j.bone.2014.08.014. Epub 2014 Aug 30.

Exome sequencing reveals a mutation in DMP1 in a family with familial sclerosing bone dysplasia.

Author information

1
Département d'Endocrinologie, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: mhcyared@terra.net.lb.
2
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Electronic address: Periklis.Makrythanasis@unige.ch.
3
Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: eliane.chouery@usj.edu.lb.
4
CNR/IRGB, UOS Milan Unit, Milan, Italy; Humanitas Clinical and Research Center, Rozzano, Milano, Italy. Electronic address: Cristina.Sobacchi@humanitasresearch.it.
5
Unité de Génétique Médicale, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Electronic address: Cybel.mehawej@net.usj.edu.lb.
6
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Electronic address: Federico.Santoni@unige.ch.
7
Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. Electronic address: Michel.Guipponi@unige.ch.
8
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, Geneva, Switzerland. Electronic address: Stylianos.Antonarakis@unige.ch.
9
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland. Electronic address: hananhamamy@yahoo.com.
10
Département d'Endocrinologie, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon; Institut Jérôme Lejeune, Paris, France. Electronic address: megarbane@usj.edu.lb.

Abstract

INTRODUCTION:

Hypophosphatemic rickets (HR) comprises a rare group of inherited diseases. Very recently, mutations in the dentin matrix protein 1 (DMP1) gene were identified in patients with an extremely rare autosomal recessive form of HR (ARHR). To date, very few cases of these mutations were reported.

MATERIALS AND METHODS:

A Lebanese consanguineous family with 2 affected sisters was studied. Patients aged 45 and 47years old presented with short stature, severe genu varum, cranial hyperostosis and a very high bone density that led to a diagnosis of a familial sclerosing bone dysplasia. Molecular analysis of known genes involved in osteopetrosis showed normal results. A combination of genotyping and exome sequencing was performed in order to elucidate the genetic basis of this pathology.

RESULTS:

Biochemical analysis was consistent with normal serum calcium and 1-25(OH)2D levels, low to normal serum phosphorus and elevated PTH values. Serum c-terminal FGF-23 was elevated in one of the two patients. A homozygous mutation disrupting the initiation codon of the DMP1 gene (OMIM 600980), NM_001079911.2: c.1A>G, p.Met1Val, was identified by exome sequencing and confirmed by Sanger sequencing.

CONCLUSION:

We report here a family of ARHR secondary to a DMP1 mutation located in the first coding exon of the gene. Our cases show that some ARHR cases may develop with age an unaccountable increase in bone density and bone overgrowth.

KEYWORDS:

DMP1; Exome; Sclerosing bone dysplasia

PMID:
25180662
DOI:
10.1016/j.bone.2014.08.014
[Indexed for MEDLINE]

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