Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families

Abstract

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.

Promoter hijack reveals pericentrin functions in mitosis and the DNA damage response

“…22 PCNT mutations have also been described in SCKL patients, 23 although the clinical features of PCNT-SCKL patients could fit with an MOPD II diagnosis. 24 Importantly, cells from PCNT-SCKL patients also show defective RT-PCR (Fig. 1C).…”

A Pericentrin-Related Protein Homolog in Aspergillus nidulans Plays Important Roles in Nucleus Positioning and Cell Polarity by Affecting Microtubule Organization

“…Notably, pericentrin mutations have been shown to be present in all MOPDII patients examined, which confirmed the genetic homogeneity of this disorder (37,48). Although the disruption of pericentrin function could contribute to human disease through multiple mechanisms, a unifying theme among the diverse deficiencies associated with pericentrin-associated disorders is the loss of microtubule integrity (5,54).…”

Identification of two novel critical mutations in PCNT gene resulting in microcephalic osteodysplastic primordial dwarfism type II associated with multiple intracranial aneurysms

“…To date, numerous mutations in this gene have been reported to cause primordial dwarfism and other disorders such as Seckel syndrome (Griffith et al 2008;Rauch et al 2008;Willems et al 2010;Unal et al 2014). Although dwarfism has been reported to be partly due to the loss of microtubule integrity function of pericentrin (Delaval and Doxsey 2010;Sam et al 2015), the genomic basis behind most clinical features of MOPD II remains unclear.…”