A homozygous SP7/OSX mutation causes osteogenesis and dentinogenesis imperfecta with craniofacial anomalies

Abstract

Introduction Osteogenesis imperfecta (OI) is a heterogeneous spectrum of hereditary genetic disorders that cause bone fragility, through various quantitative and qualitative defects of type 1 collagen, a triple helix composed of two α1 and one α2 chains encoded by COL1A1 and COL1A2, respectively. The main extra-skeletal manifestations of OI include blue sclerae, opalescent teeth and hearing impairment. Moreover, multiple genes involved in osteoblast maturation and type 1 collagen biosynthesis are now known to cause recessive forms of OI. Methods A multiplex consanguineous family of two affected males with OI was recruited for genetic screening. To determine the causative, pathogenic variant(s), genomic DNA from two affected family members were analyzed using whole exome sequencing, autozygosity mapping, and then validated with Sanger sequencing. Results We mapped a homozygous variant previously reported in SP7/OSX, a gene encoding for Osterix, a transcription factor that activates a repertoire of genes involved in osteoblast and osteocyte differentiation and function. The identified variant (c.946C > T; p.Arg316Cys) in exon 2 of SP7/OSX results in a pathogenic amino acid change in two affected male siblings and develops OI, dentinogenesis imperfecta and craniofacial anomaly. Conclusions SP7/OSX:c. 946C > T is a rare homozygous variant causing OI with extra-skeletal features in inbred Arab populations.

Novel pathogenic variants of DNAH5 associated with clinical and genetic spectra of primary ciliary dyskinesia in an Arab population

“…The two variants were assessed using different algorithms and statistical measurements to predict their pathogenicity. The first of these was rejected substitutions (RSs), defined as the number of substitutions expected under a neutral model minus the number ‘observed’ (estimated) for a particular alignment ( Pazour et al, 2006 ; Al-Mutairi et al, 2022 ; Al-Mutairi et al, 2024 ); the second was polymorphism phenotyping (PolyPhen), which is a tool to predict the possible impacts of an amino acid substitution on the structure and function of a human protein ( Adzhubei et al, 2013 ; Al-Mutairi et al, 2022 ; Al-Mutairi et al, 2024 ). The missense variant DNAH5 :c.12614G>A resulting in an amino acid exchange (p.Gly4205Glu) had RS = 5.2, PPH = 3, MedPred = 81, and Varsome: likely pathogenic, all of which indicate that the variant is highly damaging.…”

“…First, the loss of the catalytic residue is critical for ciliary targeting, and the loss of integrity of the catalytic domain in multi-ciliated respiratory cell mutants is directly related to ciliary mistargeting. This involves the targeting of cargo-containing membrane carriers or vesicles to the periciliary membrane ( Lu and Madugula, 2018 ; Al-Mutairi et al, 2022 ; Cilleros-Rodriguez et al, 2022 ; Al-Mutairi et al, 2024 ). Loss of catalytic residues for the two missense variants were significantly low and were considered pathogenic ( Tables 1 , 2 ).…”

“…The DNAH5: c.12947T>C variant leads to significant loss of stability, which is a common and widely used predictive tool for estimating the pathogenicity of missense mutations and disease development. The predicted pathogenicity from single amino acid changes affecting the thermodynamic stabilities of proteins highlights the role of protein stability in genetic diseases ( Blaabjerg et al, 2023 ; Al-Mutairi et al, 2024 ). Furthermore, the DNAH5: c.12947T>C variant has a significant loss of loop score, which estimates the pathogenicity of the missense variant on a phosphate-binding loop (P-loop) motif that is necessary for ATP binding ( Romero Romero et al, 2018 ; Al-Mutairi et al, 2024 ).…”

“…The predicted pathogenicity from single amino acid changes affecting the thermodynamic stabilities of proteins highlights the role of protein stability in genetic diseases ( Blaabjerg et al, 2023 ; Al-Mutairi et al, 2024 ). Furthermore, the DNAH5: c.12947T>C variant has a significant loss of loop score, which estimates the pathogenicity of the missense variant on a phosphate-binding loop (P-loop) motif that is necessary for ATP binding ( Romero Romero et al, 2018 ; Al-Mutairi et al, 2024 ). It is well known that axonemal dyneins are directly involved in driving ciliary movements by providing the sliding forces for the microtubules within the cilia, which require energy from ATP hydrolysis within the heavy chain domains of axonemal dyneins ( Mitchison and Mitchison, 2010 ).…”

“…For the second heterozygous variant in family KU-9 exon 77, the forward primer sequence used was 5′-AAA​CAC​TTA​CGC​CAG​AAT​CCA-3´ and reverse primer sequence used was 5′-AGT​CGA​GCT​AGC​AGC​CTG​AG-3´. The Sanger sequencing protocol was performed as described previously ( Al-Mutairi et al, 2022 ; Al-Mutairi et al, 2023 ), and the chromatograms were analysed using the GeneScreen software ( Carr et al, 2011a ; Al-Mutairi et al, 2022 ; Al-Mutairi et al, 2024 ) . The allele frequencies of the two homozygous missense variants of DNAH5 in the Arab population were estimated using the allelic discrimination test described previously ( Al-Mutairi et al, 2022 ; Al-Mutairi et al, 2023 ).…”