Pycnodysostosis is a rare genetic bone disorder (OMIM 265800) with an autosomal recessive mode of inheritance. More than 50 mutations have been reported in CTSK (Cathepsin k) responsible for this disease. Mutations in CTSK result in impaired bone resorption consequently leading to short stature, increased bone density, recurrent fractures, stubby hands and feet with dystrophic nails, unossified fontanels, and an obtuse mandibular. The present study was conducted to determine the underlying genetic cause of Pycnodysostosis in a family from Azad Kashmir, Pakistan presenting with symptoms of multiple recurrent fractures, short stature, increased bone density and stubby hands. We performed direct sequencing of CTSK for five members of the family to find out the causative mutation. All coding exons of CTSK gene were amplified and sequenced in the affected and unaffected individuals of a consanguineous Pakistani family consisting of five members, three affected brothers, one unaffected sister and the unaffected mother. We identified a known missense mutation c.136 C>T in the third exon of CTSK changing arginine to tryptophan (p.Arg46Trp) which segregated with the disorder. The clinical findingsimplicated CTSK and the use of direct sequencing provided a precise molecular diagnosis. Theidentification of the same variant in CTSK as identified in other families from Pakistan suggests that it is common due to a founder effect.
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