Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2

Budarf, Marcia L.; Konkle, Barbara A.; Ludlow, Laural B.; Michaud, Dominique; Li, Mengrong; Yamashiro, Darrell J.; McDonald‐McGinn, Donna M.; Zackai, Elaine H.; Driscoll, Deborah A.

doi:10.1093/hmg/4.4.763

Cited by 143 publications

(93 citation statements)

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“…1997; Clemetson et al, 1994;Noda et al, 1995Noda et al, , 1996Donner et al, 1996;Noris et al, 1997;Suzuki et al, 1997;Budarf et al, 1995;Ludlow, 1996); a qualitative defect of GPIba is often associated with the quantitative one (Ware et al, 1993;Margaglione et al, 1995). Mutations of the genes encoding for GPIba, GPIX and GPIbb may be responsible for this phenotype.…”

Section: Discussionmentioning

confidence: 99%

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Noris

Arbustini

Spedini³

et al. 1998

Br J Haematol

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Summary.We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIba failed to support ristocetin-induced platelet agglutination and to bind two conformationdependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIba gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters, both with severe bleeding diathesis, were homozygous for the GPIX mutation; the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele.Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIba, GPIX, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related.

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Section: Discussionmentioning

confidence: 99%

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Noris

Arbustini

Spedini³

et al. 1998

Br J Haematol

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“…To identify the causative gene(s), we performed the PPI assay in Tbx1 ϩ/Ϫ , Cdcrel1 ϩ/Ϫ , and Gnb1l ϩ/Ϫ mice. We excluded GpIb␤ from our analysis because the gene is only expressed in platelets, and in humans GPIB〉 loss of function causes Bernard-Soulier disease, a bleeding disorder that has no known association with psychiatric disease (22). The generation of Tbx1 and Cdcrel1 mutants has been reported (13).…”

Section: Ppi Analysis Of Mouse Mutantsmentioning

confidence: 99%

Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome

Paylor

Glaser

Mupo³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

297

268

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About 35% of patients with 22q11 deletion syndrome (22q11DS), which includes DiGeorge and velocardiofacial syndromes, develops psychiatric disorders, mainly schizophrenia and bipolar disorder. We previously reported that mice carrying a multigene deletion (Df1) that models 22q11DS have reduced prepulse inhibition (PPI), a behavioral abnormality and schizophrenia endophenotype. Impaired PPI is associated with several psychiatric disorders, including those that occur in 22q11DS, and recently, reduced PPI was reported in children with 22q11DS. Here, we have mapped PPI deficits in a panel of mouse mutants that carry deletions that partially overlap with Df1 and have defined a PPI critical region encompassing four genes. We then used single-gene mutants to identify the causative genes. We show that PPI deficits in Df1͞؉ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. Mutation of either gene is sufficient to cause reduced PPI. Tbx1 is a transcription factor, the mutation of which is sufficient to cause most of the physical features of 22q11DS, but the gene had not been previously associated with the behavioral͞psychiatric phenotype. A likely role for Tbx1 haploinsufficiency in psychiatric disease is further suggested by the identification of a family in which the phenotypic features of 22q11DS, including psychiatric disorders, segregate with an inactivating mutation of TBX1. One family member has Asperger syndrome, an autistic spectrum disorder that is associated with reduced PPI. Thus, Tbx1 and Gnb1l are strong candidates for psychiatric disease in 22q11DS patients and candidate susceptibility genes for psychiatric disease in the wider population.mouse model ͉ psychiatric disease ͉ DiGeorge syndrome ͉ sensorimotor gating C aused by a heterozygous multigene deletion, 22q11 deletion syndrome (22q11DS) is a relatively common genetic disorder (1:4,000 live births). Behavioral and psychiatric disorders are a prominent part of the 22q11DS phenotype. In children, these disorders include cognitive defects, anxiety, attention deficit disorder, and problems of social interaction that are increasingly recognized to meet the criteria of autistic spectrum disorder (1, 2), a neurodevelopmental disorder. In adults, high rates of psychotic disorders, especially schizophrenia, have been reported (2-5).It is likely that the pathophysiological basis of many psychiatric disorders is heterogeneous involving multiple genes and environmental factors. Therefore, when they occur frequently in association with a defined genetic defect, as in the case of 22q11DS (3, 4, 6, 7), it offers a unique opportunity to identify causative or contributing genes, especially if a good animal model is available. We developed a mouse model of 22q11DS (8), the Df1͞ϩ mouse, which carries a heterozygous deletion encompassing 22 genes. Df1͞ϩ mice recapitulate many of the cardiovascular defects associated with 22q11DS (8), and they also display abnormal behavior, including impaired sensorimotor gating, as measured by prepulse inhibition (PPI) o...

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“…On the contrary, a single case of BSS associated with a molecular defect in the GPIbb gene has been reported (Budarf et al, 1995). Until now, a defect of the GPIX gene has been shown to underlie this congenital bleeding disorder in four families (Wright et al, 1993;Clemetson et al, 1994;Noda et al, 1995a, b).…”

mentioning

confidence: 99%

A phenylalanine‐55 to serine amino‐acid substitution in the human glycoprotein IX leucine‐rich repeat is associated with Bernard‐Soulier syndrome

Noris

Şimşek

Stibbe³

et al. 1997

Br J Haematol

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Summary. The platelet membrane glycoprotein (GP) Ib-IX-V complex, the major von Willebrand factor receptor on platelets, is absent or dysfunctional in patients with the Bernard-Soulier syndrome (BSS). The four single subunits of the GPIb-IX-V complex (GPIba, Ibb, IX and V) are molecular products of different genes. Several point mutations and deletions affecting the GPIba gene have been identified as the cause of BSS, whilst in four BSS families a GPIX gene defect has been reported. Moreover, a single case of BSS has been associated with a genetic defect of GPIbb. We investigated the molecular basis of another case of BSS with a deficient expression of GPIX, as detected by immunofluorescence studies. After amplification of the entire GPIX coding region, nucleotide sequence analysis showed a homozygous single point mutation predicting a phenylalanine to serine substitution at position 55 of the mature GPIX within its unique leucine-rich repeat. By allele-specific oligonucleotide hybridization we confirmed the homozygosity of the patient as well as the carrier state of two out of three of his children studied. Although the parents of the patient, who were first cousins, were no longer alive and thus not available for study, we speculate that the molecular defect observed in the proband was inherited from both parents, who probably were heterozygous for this GPIX gene defect.This study confirms that BSS may be caused by many different subtle molecular defects that often prevent the assembly and expression of a functional GPIb-IX-V complex.

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Identification of a patient with Bernard-Soulier syndrome and a deletion in the DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2

Cited by 143 publications

References 0 publications

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: Implications for 22q11 deletion syndrome

A phenylalanine‐55 to serine amino‐acid substitution in the human glycoprotein IX leucine‐rich repeat is associated with Bernard‐Soulier syndrome

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