Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis.
Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family.


BACKGROUND
Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown.


METHODS
In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters.


CONCLUSIONS
In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation, including two brothers from a large family with a history of ADO-II in which the presence of a second ClCN7 mutation was formally excluded. Despite an early and severe clinical presentation, these five patients all reached adulthood, suggesting that the degree of dominant interference with chloride channel function can vary widely. Our findings suggest that recessive ClCN7-dependent ARO may be associated with CNS involvement and have a very poor prognosis, whereas heterozygous ClCN7 mutations cause a wide range of phenotypes even in the same family, ranging from early severe to nearly asymptomatic forms. These findings have prognostic implications, might complicate prenatal diagnosis of human osteopetroses, and could be relevant to the management of these patients.
Frattini
Annalisa
A
Istituto di Tecnologie Biomediche, CNR, Milan, Italy.
Pangrazio
Alessandra
A
Susani
Lucia
L
Sobacchi
Cristina
C
Mirolo
Massimiliano
M
Abinun
Mario
M
Andolina
Marino
M
Flanagan
Adrienne
A
Horwitz
Edwin M
EM
Mihci
Ercan
E
Notarangelo
Luigi D
LD
Ramenghi
Ugo
U
Teti
Anna
A
Van Hove
Johan
J
Vujic
Dragana
D
Young
Terri
T
Albertini
Alberto
A
Orchard
Paul J
PJ
Vezzoni
Paolo
P
Villa
Anna
A
D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005799:Genes, Dominant; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D007223:Infant; D009154:Mutation; D010022:Osteopetrosis / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011379:Prognosis; D021122:Protein Subunits / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics
C097540:CLCN7 protein, human; D018118:Chloride Channels; D021122:Protein Subunits; C472421:TCIRG1 protein, human; D025262:Vacuolar Proton-Translocating ATPases