Molecular characterization of two mutations in platelet glycoprotein (GP) Ibα in two Finnish Bernard–Soulier syndrome families

Abstract

Bernard‐Soulier syndrome (BSS) is a rare hereditary bleeding disorder and macrothrombocytopenia which is caused by a defect in the platelet glycoprotein Ib/IX/V (GP Ib/IX/V) complex, the receptor for von Willebrand factor and thrombin. Here we report the molecular basis of the classical form of BSS in two unrelated Finnish patients, both with a life‐long history of severe bleeding. Flow cytometry and immunoblotting showed no expression of GP Ib/IX, GP Ibα, GP Ibβ or GP IX (less than 10%) in the patients' platelets. No expression of GP V (<10%) was observed in propositus 1, but a residual amount was found in propositus 2 (24%). DNA sequencing analysis revealed that propositus 1 was compound heterozygous for a two‐base‐pair deletion at Tyr505(TAT) and a point mutation Leul29(CTC)Pro(CCC) in the GP Ibα gene. Propositus 2 was homozygous for the Tyr505(TAT) deletion. The nine relatives who were heterozygous for either of the mutations also had low levels of GP Ibα (74–90%). Hence, Bernard‐Soulier patients homozygous or compound heterozygous for Tyr505(TAT) are severely affected. Interestingly, both mutations have independently been found in three other families in previous reports, suggesting their ancient age or mutational ‘hot spot’.

A novel homozygous 8-base pair deletion mutation in the glycoprotein Ibα gene in a patient with Bernard–Soulier syndrome

“…The GPIba fragment was also not detected in the patient's plasma. To investigate whether different mutation types correlate with patterns of protein expression, we collected data from the previously reported patients harboring a homozygous GPIba mutation causing a premature stop codon (Table 2) [4,5,[9][10][11][12][13][14][15][16]. The GPIba protein expression profile in the present case was similar to that reported by Kanaji et al [12], who demonstrated a homozygous frameshift mutation in the GPIba gene, resulting in 294 amino acids followed by 40 altered amino acids.…”

Variant Bernard‐Soulier syndrome due to homozygous Asn45Ser mutation in the platelet glycoprotein (GP) IX in seven patients of five unrelated Finnish families

“…This has led to a very limited gene pool (47). However, whereas a single mutation accounts for almost all cases in the majority of rare genetic diseases in Finland (48,49), for some reason there are least three different BSS founder mutations (36,38, the present report).…”

“…Most of the patients with BSS have mutations unique to their families, but the Asn45Ser, Cys73Ser and Phe55Ser point mutations in the GP IX gene (30)(31)(32)(34)(35)(36)(37), as well as the Leul29Pr0, Tyr505(TA 7') and a mononucleotide deletion at position 1932-1938 in the GP Iba gene (25,27,28,(38)(39)(40), have been reported more than once in unrelated families. As a part of a larger study (36,38), we had a unique opportunity to study five apparently unrelated families with BSS, in which the BSS phenotype was due to homozygous Asn45Ser substitution in the GP IX protein.…”

Congenital macrothrombocytopenia is a heterogeneous disorder in India

“…Bernard–Soulier syndrome (BSS) and sitosterolaemia (Mediterranean stomatocytosis/macrothrombocytopenia) are classically described as recessive disorders, and heterozygous carriers of these disorders are usually asymptomatic or have mild bleeding symptoms . Supporting this, the cases studied here who were heterozygous for candidate defects in GPIBA , GPIBB and ABCG5 were either asymptomatic or had mild to moderate bleeding symptoms.…”