Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect

Abstract

Our findings expand the mutational spectrum of CTSK gene and emphasize the importance of full clinical examination of all body systems including thorough orodental evaluation in patients with pycnodysostosis.

Genetic and Molecular Evaluation: Reporting Three Novel Mutations and Creating Awareness of Pycnodysostosis Disease

“…Patients 13 and 17, who suffered recurrent fractures (3 and 9, respectively), both harbored different mutations, namely, c.436G>C and c.164A>C respectively; however, patients 12 and 16 did not have any history of recurrent fracture despite harboring the same mutation as patient 17, which suggests the absence of genotype/phenotype correlation. However, Otaify et al 2018 recorded a high incidence of pathological fractures contrary to the reports of Doherty et al [18].…”

“…Among those unusual presentations detected in our studied cohort are pancytopenia and bone marrow failure, which were the complaints of patient 7 presenting at the Hereditary Blood Disorders clinic. Reviewing the literature, pycnodysostosis patients usually suffer no change in their blood work-up, which is one of the factors that differentiates it from osteopetrosis, both being disorders of osteosclerosis [18]. Similarly, in a study of 27 benign osteopetrosis patients, whole-exome sequencing diagnosed six pycnodysostosis patients, which was the first documentation of pycnodysostosis patients suffering from pancytopenia [24].…”

“…The substitution of both glycine and serine residues at amino acid positions G146 and 297 in patients 1, 2, 7, 10, 11, 13, 14, and 18 was observed in variants in our cohort as well as in previously reported Egyptian patients, with a total of 8/19 (42.1%) patients carrying either the common p.Gly146Arg or the rare p.Ser297Asn in reported mutations of the CTSK gene. The first mutation, c.436G>C (p.Gly146Arg) characterized in 3/19 (15.8%) of the Egyptian patients and affecting the residue of the mature domain in CTSK gene, yielded a mature form of a nonfunctional protein and had been previously found in many pycnodysostosis families from diverse ethnic backgrounds: Moroccan Arab, American Hispanic, Tunisian, Algerian, and Egyptian patients [18,19,21,37,38]. The second rare reported point mutation, c. 890G>A (p.Ser297Asn) or r.785_890del causing skipping of the entire exon 7, was found in 5/19 (26.3%) of the Egyptian patients, supporting the hypotheses that this splice mutation is specific to Egyptians, and the association of this particular recurrent Egyptian mutation for different period of time supports the pan-ethnic nature of the disease.…”

Determination of the molecular mechanism by which macrophages and γδ-T cells contribute to ZOL-induced ONJ

“…The typical inflammatory factors include IL-1β, IL-12 and IL-13. Cytokines can promote each other to cause an inflammatory cascade reaction, aggravate tissue damage, and participate in bone metabolism [ 19 , 20 ]. Chemokines can regulate inflammation.…”

Multiple Fractures and Impaired Bone Fracture Healing in a Patient with Pycnodysostosis and Hypophosphatasia

“…The protease CTSK is essential for the bone-resorbing osteoclasts (OC) to degrade bone matrix proteins, and impairment leads to failure of bone resorption and remodelling [4][5][6][7]. The clinical presentation is characterized by brittle bones, small stature, craniofacial and oral abnormalities, including micrognathia and dental crowding [8,9].…”