A novel large fragment deletion in PLS3 causes rare X-linked early-onset osteoporosis and response to zoledronic acid

Abstract

We identified a large fragment deletion mutation in PLS3 for the first time and elucidated the possible mechanism of the deletion, which led to X-linked early-onset osteoporosis and multiple vertebral fractures. Our findings would enrich the etiology spectrum of this rare disease.

A novel nonsense variant in PLS3 causes X‐linked osteoporosis in a Chinese family

“…To date, including the novel variant in our study, only eight pathogenic variants in PLS3 were confirmed in X‐linked osteoporotic patients (Figure d) (Laine et al., ; Lv et al., ; van Dijk et al., ). All of the previously reported patients with PLS3 variants did not have extraskeletal manifestations.…”

“…There are eight pathogenic variants in PLS3 associated with osteoporosis to date (Figure d) (Kannu et al., ; Laine et al., ; Lv et al., ; van Dijk et al., ). However, most of them led to degradation of PLS3 mRNA through the NMD mechanism (Strachan & Read, 2010).…”

Novel PLS3 variants in X‐linked osteoporosis: Exploring bone material properties

“…Since its first description of PLS3‐osteoporosis in five families with apparent X‐linked osteoporosis, there have been other case reports adding to the literature and expanding the phenotype of this condition (Dijk et al, ; Laarschot et al, ; Kannu et al, ; Lv et al, ; Kämpe et al, ). From the literature so far and corroborated by our patients, the phenotype consists of vertebral compression fractures, peripheral including long bone fractures and low BMD but without features such as blue sclerae, short stature, joint hyperlaxity, or facial features typical of “Classical OI” which is helpful in terms of genotype‐phenotype correlation.…”

Plastin 3 in X-Linked Osteoporosis: Imbalance of Ca2+-Dependent Regulation Is Equivalent to Protein Loss

“…To date, 27 OI-associated pathogenic variants (including coding mutations and gene deletions/truncations) have been identified in the PLS3 gene located on the X chromosome ( Table 1). The majority of these are expected to result in the absence of functional protein: four full or partial PLS3 gene deletions (Kämpe et al, 2017a;Kannu et al, 2017;Lv et al, 2017), seven frame-shift mutations resulting in truncated mRNA constructs (Fahiminiya et al, 2014;Nishi et al, 2016;Kämpe et al, 2017a,b;Lv et al, 2017), six nonsense mutations (Fahiminiya et al, 2014;Kämpe et al, 2017b;Balasubramanian et al, 2018;Chen et al, 2018;Wang et al, 2020), and one aberrant splicing variant (Cao et al, 2019). All but two of the resulting truncated mRNA molecules appear to be the canonical substrates for degradation by nonsense-mediated mRNA decay (NMD) (Miller and Pearce, 2014;Kishor et al, 2019).…”

“…Vertebrae compression fractures, as well as long bone fractures resulting from minor trauma are common. In more severe cases, phenotypes can include facial dismorphism, clumsy gait, joint hyperlaxity, kyphosis, deafness, and blue sclerae (Fahiminiya et al, 2014;Nishi et al, 2016;Kämpe et al, 2017a,b;Lv et al, 2017;Chen et al, 2018;Costantini et al, 2018;Cao et al, 2019;Hu et al, 2020).…”