SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome

Abstract

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo–tracheo–esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of ‘SPECC1L syndrome’ to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo–tracheo–esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification.

SPECC1L binds the myosin phosphatase complex MYPT1/PP1β and can regulate its distribution between microtubules and filamentous actin

“…7 C ). Mutations in this region in SPECC1L have been identified in patients with the congenital developmental disorders Opitz G/BBB and Teebi hypertelorism ( 27 , 28 , 29 , 30 ) ( Fig. 7 B ), and previous studies suggested that disrupted MT association may contribute to the observed phenotypes.…”

“…Although not studied to the same extent, depletion of SPECC1L in cells led to defects in cytoskeletal organization, cell division, and migration ( 25 , 26 ), and SPECC1L mutations have been linked to developmental facial morphogenesis disorders that result in congenital malformations ( 25 , 27 , 28 , 29 , 30 ). The protein is found predominantly in the cytoplasm and has been shown to accumulate at both MT and filamentous actin structures throughout the cell cycle ( 25 , 31 ).…”

SPECC1L binds MYPT1/PP1β and can regulate its distribution between microtubules and filamentous actin

“…S5c). Mutations in this region in SPECC1L have been identified in patients with the congenital developmental disorders Opitz G/BBB and Teebi hypertelorism [26]–[29] (Fig. 7a), and previous studies suggested that disrupted MT association may contribute to the observed phenotypes.…”

“…Although not studied to the same extent, depletion of SPECC1L in cells led to defects in cytoskeletal organization and cell migration [25], and SPECC1L mutations have been linked to developmental facial morphogenesis disorders that result in congenital malformations [25]- [29].…”

“…Although not studied to the same extent, depletion of SPECC1L in cells led to defects in cytoskeletal organization and cell migration[25], and SPECC1L mutations have been linked to developmental facial morphogenesis disorders that result in congenital malformations [25]–[29]. The protein is found predominantly in the cytoplasm and has been shown to accumulate at both microtubule (MT) and filamentous actin structures throughout the cell cycle [25][30].…”