NovelPOC1Amutation in primordial dwarfism reveals new insights for centriole biogenesis

Abstract

POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related to the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed at identifying the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of whole-exome sequencing. A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed the gene expression array and compared their expression profiles to those of control fibroblast cells. The gene expression array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in the extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused the formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A were accompanied by alterations in another centrosome-associated WD repeat protein p80-katanin. As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes the formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement.

Truncation of POC1A associated with short stature and extreme insulin resistance

“…The growth parameters, facial dysmorphism and skeletal features of the proband in this report are highly similar to other published cases (Koparir et al 2015), and although the large majority of patients reported to date are of prepubertal age, one other patient has been described with precocious puberty (Koparir et al 2015), which may play a role in the short final height of the proband we describe. There are significant phenotypic differences among patients reported to date, however, Most prominently, the proband we describe had no ectodermal dysplasia, reported in three of four families to date (Koparir et al 2015; Shaheen et al 2012), and, conversely, did have extreme, dyslipidaemic insulin resistance, which was not clearly described in other reports. Differing genetic backgrounds may contribute to these differences, as suggested by the occurrence of type 2 diabetes of onset in middle age in several members of the family we describe, albeit without the extreme insulin resistance of the proband.…”

“…We identified 7 rare, functional homozygous variants, among which was a frameshift mutation in POC1A , which was associated during the course of our study by three groups with a similar syndrome in five consanguineous families from the Middle East (Koparir et al 2015; Sarig et al 2012; Shaheen et al 2012). Three of these families harboured one of two missense mutations (Koparir et al 2015; Sarig et al 2012), while the other three families had in common an early nonsense mutation, although cellular studies suggested significant translational readthrough of the mutation (Shaheen et al 2012). …”

“…As mutations in POC1A have been associated with centrosome amplification (Koparir et al 2015; Sarig et al 2012; Shaheen et al 2012), we next examined centrosome number in the proband’s fibroblasts using immunostaining with antibody against ALMS1, a protein localized to the proximal ends of centrioles (Knorz, et al 2010). About 12% of interphase cells showed centrosomal amplification with centrosome number ranging from 3 to 10 per cell.…”

“…A new form of primordial dwarfism caused by a homozygous genetic defect in the luminal centriolar protein POC1A was recently described (Koparir, et al 2015; Sarig, et al 2012; Shaheen, et al 2012), and we now add to this by reporting a further affected patient with a frameshift mutation predicted to affect 2 out of 3 POC1A isoforms. This was associated with supernumerary centrosomes and multipolar mitotic spindles in primary cells, and with sustained and extreme dyslipidaemic insulin resistance.…”

“…Some of the phenotypic differences may alternatively be explained by the differing nature of the POC1A mutations involved in each report: previous cases were attributed to POC1A hypomorphism due to partial readthrough of a premature nonsense mutation in one report (Shaheen et al 2012), and to rare missense mutations in two others (Koparir et al 2015; Sarig et al 2012). In all cases all protein products of the gene were predicted to be affected.…”