Dominant missense mutations in FLNB, encoding the actin-cross linking protein filamin B (FLNB), cause a broad range of skeletal dysplasias with varying severity by an unknown mechanism. Here these FLNB mutations are shown to cluster in exons encoding the actin-binding domain (ABD) and filamin repeats surrounding the flexible hinge 1 region of the FLNB rod domain. Despite being positioned in domains that bind actin, it is unknown if these mutations perturb cytoskeletal structure. Expression of several full-length FLNB constructs containing ABD mutations resulted in the appearance of actin-containing cytoplasmic focal accumulations of the substituted protein to a degree that was correlated with the severity of the associated phenotypes. In contrast, study of mutations leading to substitutions in the FLNB rod domain that result in the same phenotypes as Additional Supporting Information may be found in the online version of this article.
The excessive proteolysis of vWF in PAH is likely to be related to an increased susceptibility of vWF to proteases induced by high shear rates rather than to an enhanced release of enzymes.
A heat-treated factor VIII (F VIII) concentrate (Haemate P) has been administered to patients with various types of von Willebrand's disease (vWD). The 4 activities of F VIII/vWF as well as change in the multimeric structure of vWF were then studied. In 4 patients with type I vWF who were given a Ristocetin cofactor (Rcof) dose of 42-78 U/kg, there was a clear reduction of the bleeding time and an increase of F VIII: C, F VIII: Ag, Rcof and vWF: Ag for several hours. The recovery of Rcof. after 1 h was 50-75%. Although the multimeric composition of vWF in these patients was similar to that of normal plasma, the density of each multimer band was very low. After infusion, however, the density of all multimer bands increased for several hours, to decrease again after 24 h. In 4 patients with type II A vWD who received a dose of Rcof of 55-76 U/kg, the 4 activities of F VIII/vWF increased similarly as was the case in type I. All patients had only 3-4 smaller multimer bands. New larger and intermediate multimers appeared for several hours after infusion of the preparation. Two patients with type III vWD who received doses of Rcof of 52 and 65 U/kg showed also a similar increase in the 4 activities of F VIII/vWF after infusion. All the multimers lacking in these patients appeared for several hours after infusion.
We report here on two unrelated patients (Patients 1 and 2) with a cryptic microduplication involving a 22q13 segment. Both patients manifested infantile hypotonia, developmental delay, and growth deficiency. In addition, an abnormal signal intensity area was detected in the frontal white matter of Patient 2 by brain MRI. Whole-genome microarray comparative genomic hybridization for Patient 1 and fluorescence in situ hybridization analysis with 22q-subtelomeric probes performed in both patients showed a submicroscopic 22q13 duplication that involved the SHANK3 gene. The duplication in Patient 1 was de novo type, while that in Patient 2 was derived from a familial 17;22 translocation. The presence of common clinical manifestations in the two patients with the common duplicated region led to a conclusion that 22q terminal duplication is a recognizable clinical entity, that is, the 22q13 microduplication syndrome.
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