Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region

Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region

Author Araujo, Thais Fenz Google Scholar
Ribeiro, Erlane Marques Google Scholar
Arruda, Anderson Pontes Google Scholar
Moreno, Carolina Araujo Google Scholar
Vasconcelos de Medeiros, Paula Frassinetti Google Scholar
Minillo, Renata Moldenhauer Google Scholar
Melo, Debora Gusmao Google Scholar
Kim, Chong Ae Google Scholar
Rodovalho Doriqui, Maria Juliana Google Scholar
Felix, Temis Maria Google Scholar
Fock, Rodrigo Ambrosio Autor UNIFESP Google Scholar
Cavalcanti, Denise Pontes Google Scholar
Abstract Background: Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceara State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis. Methods: The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceara, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents. Results: We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceara State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceara (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceara have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast. Conclusions: The high frequency of pycnodysostosis in Ceara State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceara, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceara, suggestive of a founder effect.
Keywords Pycnodysostosis
Cathepsin K
Inbreeding
Novel mutation
Language English
Sponsor CNPq [402008/2010-3, 590148/2011-7]
CAPES [3300017023p6]
Fapesp [2015/22145-6]
Grant number CNPq:402008/2010-3
590148/2011-7
CAPES: 3300017023p6]
FAPESP:2015/22145-6
Date 2016
Published in European Journal Of Medical Research. London, v. 21, p. -, 2016.
ISSN 0949-2321 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent -
Origin http://dx.doi.org/10.1186/s40001-016-0228-7
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000381782800001
URI http://repositorio.unifesp.br/handle/11600/51161

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