Genetic analysis of autosomal recessive osteopetrosis in Chuvashiya: the unique splice site mutation in TCIRG1 gene spread by the founder effect.

Published on Jan 28, 2009in European Journal of Human Genetics3.657
· DOI :10.1038/EJHG.2008.234
E. A. Bliznetz6
Estimated H-index: 6
(Academy of Medical Sciences, United Kingdom),
Svetlana M Tverskaya1
Estimated H-index: 1
(Academy of Medical Sciences, United Kingdom)
+ 6 AuthorsAlexander V. Polyakov10
Estimated H-index: 10
(Academy of Medical Sciences, United Kingdom)
Sources
Abstract
The rare malignant disorder autosomal recessive osteopetrosis (OPTB) is one of the most prevalent autosomal recessive diseases in the Chuvash Republic of Russia. The purpose of this study was to determine the underlying molecular cause of osteopetrosis in Chuvashiya and to reveal the factors causing the unusual high frequency of the disease in this region. Having assumed a founder effect, we performed linkage disequilibrium (LD) mapping of the OPTB locus at the TCIRG1 region and found a unique splice site mutation c.807+5G>A in all Chuvashian OPTB patients studied. We then analyzed the mutational change in mRNA and detected an intron insertion within the mutant transcript, resulting in a frameshift and premature stop-codon formation (p.Leu271AspfsX231). A decreased expression of the mutant transcript was also detected, which may have been the result of nonsense-mediated decay. Real-time qPCR and MLPA® melting curve analysis-based systems were designed and used for c.807+5G>A mutation screening. In addition to analyzing the gene frequency in Chuvashiya, we also estimated three other populations in the Volga-Ural region (Mari, Udmurt and Bashkir). We found a 1.68% prevalence in Chuvashiya (calculated disease frequency, 1/3500 newborns) and a 0.84% in the Mari population (1/14 000 newborns). The haplotype analysis revealed that all OPTB cases in Chuvashians and Marians originated from a single mutational event and the age of the mutation in Chuvashians was estimated to be approximately 890 years.
Figures & Tables
Download
📖 Papers frequently viewed together
72 Citations
276 Citations
160 Citations
References25
Newest
#1Jens C. FuhrmannH-Index: 8
#2Philipp F. LangeH-Index: 19
Last. Thomas J. JentschH-Index: 99
view all 4 authors...
Source
#1Anastasiya V. Kazantseva (UMMS: University of Massachusetts Medical School)H-Index: 1
#2Andrey Goltsov (MSU: Moscow State University)H-Index: 6
Last. Evgeny I. RogaevH-Index: 41
view all 11 authors...
The molecular mechanisms controlling human hair growth and scalp hair loss are poorly understood. By screening about 350,000 individuals in two populations from the Volga-Ural region of Russia, we identified a gene mutation in families who show an inherited form of hair loss and a hair growth defect. Affected individuals were homozygous for a deletion in the LIPH gene on chromosome 3q27, caused by short interspersed nuclear element–retrotransposon–mediated recombination. The LIPH gene is express...
195 CitationsSource
#1Philipp F. Lange (UHH: University of Hamburg)H-Index: 19
#2Lena Wartosch (UHH: University of Hamburg)H-Index: 7
Last. Jens C. Fuhrmann (UHH: University of Hamburg)H-Index: 8
view all 4 authors...
Mutations in ClC-7, a late endosomal/lysosomal member of the CLC family of chloride channels and transporters1,2, cause osteopetrosis3 and lysosomal storage disease4 in humans and mice. Severe osteopetrosis is also observed with mutations in the OSTM1 gene, which encodes a membrane protein of unknown function5. Here we show that both ClC-7 and Ostm1 proteins co-localize in late endosomes and lysosomes of various tissues, as well as in the ruffled border of bone-resorbing osteoclasts. Co-immunopr...
284 CitationsSource
#1W BalemansH-Index: 8
#2L. Van WesenbeeckH-Index: 3
Last. W. Van HulH-Index: 29
view all 3 authors...
The osteopetroses are a heterogeneous group of bone remodeling disorders characterized by an increase in bone density due to a defect in osteoclastic bone resorption. In humans, several types can be distinguished and a classification has been made based on their mode of inheritance, age of onset, severity, and associated clinical symptoms. The best-known forms of osteopetrosis are the malignant and intermediate autosomal recessive forms and the milder autosomal dominant subtypes. In addition to ...
170 CitationsSource
#1Lucia SusaniH-Index: 14
Last. Franco Pagani (International Centre for Genetic Engineering and Biotechnology)H-Index: 34
view all 12 authors...
Human malignant infantile osteopetrosis (arOP) is a genetically heterogeneous autosomal recessive disorder of bone metabolism. The TCIRG1 gene, encoding the a3 subunit of the vacuolar proton pump, which mediates the acidification of the bone/osteoclast interface, is responsible for more than one-half of the arOP patients. We performed genetic analysis of TCIRG1 in 55 arOP patients including 25 new cases and identified nine novel mutations. The two most frequent mutations, c.1674–1G>A (aberrant s...
115 CitationsSource
#1Youn-Jeong Shin (SNU: Seoul National University)H-Index: 1
#2So Eun Park (SNU: Seoul National University)H-Index: 1
Last. Annalisa FrattiniH-Index: 1
view all 9 authors...
Chloride Channel CICN7 Mutations in a Korean Patient with Infantile Malignant Osteopetrosis Initially Presenting with Neonatal Thrombocytopenia
7 CitationsSource
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. Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe...
240 CitationsSource
#1Nader Chalhoub (UdeM: Université de Montréal)H-Index: 4
#2Nadia Benachenhou (UdeM: Université de Montréal)H-Index: 4
Last. Jean Vacher (UdeM: Université de Montréal)H-Index: 15
view all 8 authors...
The spontaneous mouse grey-lethal (gl) mutation is responsible for a coat color defect and for the development of the most severe autosomal recessive form of osteopetrosis. Using a positional cloning approach, we have mapped and isolated the gl locus from a approximately 1.5 cM genetic interval. The gl locus was identified in a bacterial artificial chromosome (BAC) contig by functional genetic complementation in transgenic mice. Genomic sequence analysis revealed that the gl mutation is a deleti...
302 CitationsSource
#1Katrien Janssens (University of Antwerp)H-Index: 19
#2Wim Van Hul (University of Antwerp)H-Index: 50
Bone remodelling is an important process both throughout growth and in adult life. The homeostasis of bone tissue is maintained by the balanced processes of bone resorption and formation. Imbalance can give rise to a broad spectrum of skeletal pathologies, of which osteoporosis, characterized by a decrease in bone density leading to increased fracture risk, is the best known because of its high prevalence and consequently high socio-economic impact. At the opposite end of the spectrum, several g...
106 CitationsSource
#1Erna Cleiren (University of Antwerp)H-Index: 8
#2Olivier Benichou (University of Paris)H-Index: 28
Last. Wim Van HulH-Index: 50
view all 12 authors...
Albers-Schonberg disease, or autosomal dominant osteopetrosis, type II (ADO II), is the most common form of osteopetrosis, a group of conditions characterized by an increased skeletal mass due to impaired bone and cartilage resorption. Following the assignment of the gene causing ADO II to chromosome 16p13.3, we now report seven different mutations in the gene encoding the CICN7 chloride channel in all 12 ADO II families analysed. Additionally, a patient with the severe, autosomal recessive, inf...
438 CitationsSource
Cited By18
Newest
#1Ehud Even-Or (HUJI: Hebrew University of Jerusalem)H-Index: 4
#2Polina Stepensky (HUJI: Hebrew University of Jerusalem)H-Index: 28
Malignant infantile osteopetrosis (MIOP) is a rare hereditary disorder characterized by excessive bone overgrowth due to a defect in bone marrow resorption by osteoclasts. In most cases, hematopoietic stem cell transplantation (HSCT) may correct bone metabolism but the rapidly progressing nature of this condition necessitates early diagnosis and prompt treatment to minimize irreversible cranial nerve damage. The management of patients with MIOP presents many unique challenges. In this review, th...
Source
#1Georgii P. Romanov (North-Eastern Federal University)H-Index: 3
#2Vera G. Pshennikova (North-Eastern Federal University)H-Index: 3
Last. Nikolay A. Barashkov (North-Eastern Federal University)H-Index: 8
view all 12 authors...
Source
#1A.E. Burya (RSMU: Russian National Research Medical University)
Last. E V Skorobogatova (RSMU: Russian National Research Medical University)H-Index: 7
view all 7 authors...
Generalized osteopetrosis is a rare hereditary disease characterized by impairment of skeleton bones formation, bone marrow dysfunction, neurologic deficiency and blindness. The main treatment for osteopetrosis is an allogeneic hematopoietic stem cell transplantation (allo-HSCT). To review and analyze experience of Department of bone marrow transplantation of RDKB (BMT RDKB) of allo-HSCT for patients with autosomal recessive generalized osteopetrosis; to evaluate tolerability and efficacy of the...
Source
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disease characterized by a combination of hearing impairment with preauricular pits, cervical fistulas or cysts, and various renal abnormalities. Mutations in the EYA1 gene are responsible for 40% of BOR syndrome cases. This study for the first time demonstrates a detailed clinical description and molecular genetic study of BOR syndrome in the Russian Federation among eight Russian patients from four unrelated families. As a result, two ...
1 CitationsSource
#1Polina Stepensky (HUJI: Hebrew University of Jerusalem)H-Index: 28
#2Sigal Grisariu (HUJI: Hebrew University of Jerusalem)H-Index: 10
Last. Ansgar SchulzH-Index: 42
view all 15 authors...
Osteopetrosis (OP) is a rare disease caused by defective osteoclast differentiation or function. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available in the infantile “malignant” form of OP. Improved clinical and genetic diagnosis of OP has seen the emergence of a cohort of patients with less severe and heterogeneous clinical presentations. This intermediate form of OP does not call for urgent intervention, but patients accumulate debilitating skeletal complica...
6 CitationsSource
#1P. GundorovaH-Index: 4
#2Rena A. Zinchenko (RSMU: Russian National Research Medical University)H-Index: 9
Last. Aleksander V. PolyakovH-Index: 2
view all 6 authors...
Phenylketonuria is an inherited disease caused by mutations in the phenylalanine hydroxylase gene PAH. Different PAH pathogenic variants occur in different ethnic groups with various frequencies and the incidence of the disease itself varies from country to country. In the Caucasus region of Russia, some ethnoses are geographically and culturally isolated from each other. The tradition of monoethnic marriages may cause decreased genetic variability in those populations. In the Karachay-Cherkess ...
8 CitationsSource
#1Bella Shadur (UNSW: University of New South Wales)H-Index: 6
#2Irina ZaidmanH-Index: 7
Last. Polina StepenskyH-Index: 12
view all 9 authors...
BACKGROUND: Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients...
14 CitationsSource
#1O. L. MironovichH-Index: 1
#2E. A. BliznetzH-Index: 6
Last. Alexander V. PolyakovH-Index: 10
view all 10 authors...
: Cisplatin and its derivatives are widely used chemotherapeutic agents for the treatment of many cancers, including hepatoblastoma, brain tumors, and germ-cell tumors. This therapy contributed to the dramatic increase in the survival rate. However, its use is restricted by the high incidence of irreversible ototoxicity associated with cisplatin application (in more than 60% of the children receiving it). Some studies have reported that genetic variants of TPMT (rs 12201199), COMT (rs4646316), a...
4 CitationsSource
#1Muhammad AjmalH-Index: 13
#2Asif Mir (IIUI: International Islamic University, Islamabad)H-Index: 13
Last. Muhammad Ali NasirH-Index: 9
view all 9 authors...
Background Osteopetrosis is a rare inherited bone disorder mainly described as an increased bone density caused by defective osteoclastic bone resorption. To date, genetic variants of eleven genes have been reported so far to be associated with different types of osteopetrosis. However, malignant infantile osteopetrosis, a lethal form of the disease, is mostly (50%) caused by mutation(s) in TCIRG1 gene. In this study, we investigated a consanguineous Pakistani family clinically and genetically t...
3 CitationsSource