Pericentrin which is encoded by PCNT gene is a large coiled-coil protein localizes to the centrosome(Doxsey, Stein et al. 1994). The PCNT gene is located on chromosome 21q22.3 and containes 47 coding exons (Fig. 1A). This gene spans ∼122 kb of human genomic sequence. Pericentrin is composed of 3336-amino acid (Fig. 1G) and has a crucial role in regulation of cell cycle and the mitotic spindle(Zimmerman, Sillibourne et al. 2004) Pericentriolar material (PCM) is an organization that regulates centriole involvement during mitosis cell division. The PCM contains components like theγ -tubulin ring complex (γ-TuRC) binds to PACT domain in Pericentrin (Dictenberg, Zimmerman et al. 1998). The PACT domain (a.a 3139–3216) is present near the C-terminus of Pericentrin and remained highly conserved during evolution (Gillingham and Munro 2000, Watanabe, Takao et al. 2019). Loss of function Mutations in PCNT gene result in perturbation of cell proliferation associated with reduction of brain and body size (Dehghan Tezerjani, Vahidi Mehrjardi et al. 2020). Mutations in PCNT gene is contributed to the phenotype of MOPD II .A wide range of clinical abnormalities, including skeletal dysplasia, microcephaly, abnormal skin pigmentation, Insulin resistance, typical facial features, and severe tooth deformities are reported in MOPDII (Majewski, Goecke et al. 1982, Hall, Flora et al. 2004, Bober, Khan et al. 2010). Here, we introduced three Iranian patients with hallmarks of MOPDII. There were two girls, ages 3 and 4, and a 2-year-old boy. Their clinical information indicates that all of these patients were born as a result of consanguineous marriage. There are common clinical characteristics among Primordial dwarfism (PD) subtypes(Liu, Tao et al. 2021); therefore, mutation analysis is deemed essential for the precise diagnosis and validation of MOPD II. WES as a powerful and cost effective method leads to identify relevant genetic causes in rare and heterogeneous genetic disorders (Garshasbi, Mahmoudi et al. 2020). MOPD II has clinical symptoms that are comparable to other disorders such as Seckel syndrome. MOPDII patients have more sever growth retardation and skeletal abnormalities than Seckel patients, but Mental retardation which is a characteristic of Seckel syndrome is absent in MOPII (Willems, Genevieve et al. 2010).Most of the Seckel patients manifest the disorder due to ATR gene mutations; however, several Seckel patients were reported with PCNT mutations (Griffith, Walker et al. 2008, Willems, Genevieve et al. 2008).
Hitherto, over 50 pathogenic mutations have been reported across the PCNT gene with no hot-spot region (Dieks, Baumer et al. 2014). Using WES, we succeeded to identify a nonsense homozygous variant in PCNT gene (c.2812 C > T, p.Gln 938*) in case 1 and 2. Discovery of the c.2812 C > T variant in exon 15 of the PCNT gene in cases 1 and 2, who referred from different parts of Iran can escalate this notion that this variant has high frequency in the Iranian population; nonetheless, more research is required.
In another case (2-year-old boy), at the first, an insertion (c.3836_ 3837 ins17) in exon19 of PCNT gene was suggested based on WES analysis. However it was not validated after amplification of the region and Sanger sequencing. GAP-PCR method revealed a novel homozygous 384bp deletion flanking entire exon19 of PCNT gene. Deletion of exon19 leads to a premature truncation in Pericentrin protein. Our results in the current article suggest that premature stop codons p.Pro1204Glyfs*11 and p.Gln 938* create non-functional truncated pericentrin protein without PACT domain (Fig. 1H and I).
Missense mutation c.3840G > C in the last base of exon19 has been reported previously to be related to Seckel syndrome(Willems, Genevieve et al. 2010). This mutation can alter the splicing process and exon 19 skipping of PCNT gene. Here we introduce deletion exon19 in a MOPDII patient for the first time.
Defining the genetic causes of PD would be beneficial for understanding the mechanisms involved in its various subtypes and better diagnosis and their classifications. Also as the rate of consanguineous marriage is relatively high in our country in specific regions this finding will be very important for determining the founder mutations and carriers of the genetic defects for preventing the disease running in the families and also developing a genetic screening panel for diagnosis and accurate treatment of the disease avoiding growth hormone administration