The same genetic defect in three Tunisian families with Bernard Soulier syndrome: a probable founder Stop mutation in GPIbbeta

Abstract

GPIbα, GPIbβ, and GPIX are three candidate genes for a rare genetic bleeding disorder named Bernard Soulier syndrome (BSS). These genes are unique in the genome and encode for glycoprotein subunits of the GPIb-IX complex. Quantitative or qualitative deficiency in this complex is often associated with BSS. Here, we report the novel variant of BSS in which Ser23 of GPIbβ is substituted by a Stop codon causing a premature termination of translation, recently described in one family. This genetic defect is revealed in three unrelated BSS patients. The pedigree was determined for two families (F1 and F2) and revealed the homozygosity of the mutation in the two patients and its heterozygosity in parents. In the third family, the patient DNA was heterozygote with the same Ser23 Stop mutation in addition to two missense heterozygote mutations (Asp 51 Gly) and (Ala 55 to Pro). We studied the effect of the Ser23 Stop mutation on the expression of the complex. Our findings confirm that the identified GPIbβ mutation is responsible for the BSS phenotype and hampers the GPIb-IX complex to form on the platelets' surface. Regarding the scarcity of the BSS syndrome, the occurrence of the same mutation in three unrelated families would suggest a BSS founder mutation in Tunisia.

Spectrum of the Mutations in Bernard-Soulier Syndrome

“…In three of these families, more than one variant per allele was identified (Supp. Table S1): in the first family (BSS3), the affected individuals were homozygous for two GP1BA mutations; in the second (BSS103), the patient was heterozygous for three different GP1BB mutations [Hadjkacem et al, 2010]; and in the third (BSS99), the patient was homozygous for two GP1BB and heterozygous for one GP1BA mutation [Sumitha et al, 2011]. Consistent with the rarity of the disease, 179 (85%) were homozygous and 28 (13%) were compound heterozygous for mutations in one of the three genes.…”

Asymptomatic Bernard-Soulier Syndrome With a Novel Mutation

“…A 13-bp deletion of the signal peptide coding sequence leading to premature termination has been found [15,16]. Ser stop in the GPIBB gene have been reported in three Tunisian families [17]. Ten novel mutations were identified in India.…”

“…Int J Clin Pediatr. 2020;9(1): [16][17][18][19] platelet counts were 38,000, 41,000, 51,000, 15,000, 45,000 and 56,000/µL, the blood film showed reduced number of platelets with large and giant platelets ( Table 1). Opinion of the pediatric hematologist was taken.…”

Bernard Soulier Syndrome: A Genetic Bleeding Disorder

“…Subsequently, our study included two other unrelated Tunisian families with BSS cases. In one of these families, we have revealed the same Ser23Stop mutation while in the second we observed compound heterozygosity including Ser23Stop in addition to two others missense mutations located in GPIbβ gene: Asp51Gly and Ala55Pro (Hadjkacem et al, 2010b). Given that most of described BSS mutations are unique and the same Ser23Stop mutation being found in three unrelated Tunisian families, we suggested that it is an ancient mutation having a founder effect and can be used in genotyping for BSS diagnosis in further exploration of other Tunisian families.…”

“…Flow cytometric analysis of normal and BSS platelets. (Hadjkacem et al, 2010b) HIP8 is an antibody recognizing GPIIb-IIIa complex and serves as positive control. HIP1, MB45 and SZ2 are antibodies directed against different epitope on GPIbα.…”