Molecular analysis of the reciprocal chromosomal translocation t(12;22)(p11.2;q13.3) cosegregating with a complex type of synpolydactyly showed involvement of an alternatively spliced exon of the fibulin-1 gene (FBLN1 located in 22q13.3) and the C12orf2 (HoJ-1) gene on the short arm of chromosome 12. Investigation of the possible functional involvement of the fibulin-1 protein (FBLN1) in the observed phenotype showed that FBLN1 is expressed in the extracellular matrix (ECM) in association with the digits in the developing limb. Furthermore, fibroblasts derived from patients with the complex type of synpolydactyly displayed alterations in the level of FBLN1-D splice variant incorporated into the ECM and secreted into the conditioned culture medium. By contrast, the expression of the FBLN1-C splice variant was not perturbed in the patient fibroblasts. Based on these findings, we propose that the t(12;22) results in haploinsufficiency of the FBLN1-D variant, which could lead to the observed limb malformations.T he formation of digits is a complex, tightly regulated process which involves apoptosis and in which several pathways and signalling molecules are involved. The presentation of a small family with a very specific congenital hand malformation associated with an apparently balanced autosomal reciprocal translocation provided us with the opportunity to identify novel genes involved in limb development. Previously, we described the clinical phenotype of three patients from one family sharing a complex type of synpolydactyly (fig 1) associated with a constitutional balanced t(12;22)(p11.2;q13.3) and the exclusion of synpolydactyly associated HOXD13 mutations in these patients.
Heterotaxia is an aetiologically heterogeneous condition caused by an abnormal left-right axis formation, resulting in reversed left-right polarity of one or more organ systems. In a patient with heterotaxia and a de novo reciprocal translocation t(6;18)(q21;q21), we found that the PA26 gene was disrupted by the 6q21 breakpoint. Northern blot analysis showed decreased expression of the PA26 gene in an Epstein-Barr virus-transformed cell line of this patient. During early embryogenesis of Xenopus, the orthologue of PA26, XPA26 is exclusively expressed in the notochord, a midline structure. This further supports a possible role of PA26 in human situs determination. Mutation analysis of human PA26 gene in 40 unrelated individuals with unexplained heterotaxia failed to identify mutations, indicating that PA26 mutations are not a frequent cause of heterotaxia in humans. Analysis of the PA26 gene structure resulted in the identification of a novel PA26-related gene family, which we have named the sestrin family, and which comprises three closely related genes in human and in mouse.
To further explore the allelic heterogeneity within the group of LEMD3-related disorders, we have screened a larger series of patients including 5 probands with osteopoikilosis or Buschke-Ollendorff syndrome (BOS), 2 families with the co-occurrence of melorheostosis and BOS, and 12 unrelated patients with isolated melorheostosis. Seven novel LEMD3 mutations were identified, all predicted to result in loss-of-function of the protein. We confirm that loss-of-function mutations in the LEMD3 gene can result in either osteopoikilosis or BOS. However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis. The additional presence of osteopoikilosis lesions in these patients seemed to distinguish them from the group of sporadic melorheostosis patients where no germline LEMD3 mutation was identified. Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown.
Mutations of UFD1L Are Not Responsible for the Majority of Cases of DiGeorge Syndrome/ Velocardiofacial Syndrome without Deletions within Chromosome 22q11 To the Editor: Deletions of chromosome 22q11 are associated with a wide spectrum of congenital malformation, encompassed by the acronym "CATCH22" (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia on chromosome 22), including velocardiofacial syndrome (VCFS; MIM 192430), DiGeorge syndrome (DGS; MIM 188400), and conotruncal-anomaly face (Emanuel et al. 1998). The major anomalies include outflow-tract congenital heart defects, hypoplasia of the parathyroids and thymus, craniofacial dysmorphism, and learning/behavioral problems (Ryan et al. 1997). Many of these are thought to be due to a defective neural-crest contribution during development. The DiGeorge chromosomal region (DGCR) is entirely cloned (Carlson et al. 1997) and sequenced, and several genes have been reported mapping to the region. Mutation screens of genes mapping to the proximal end of this region, termed the "minimal DiGeorge chromosomal region" (MDGCR; Gong et al. 1996), have been negative (Wadey et al. 1995; Gong et al. 1997; Gottlieb et al. 1997; Lindsay et al. 1998). Attention therefore has turned to the regions adjacent and distal to the MDGCR. Recently, the gene UFD1L was proposed as the major gene haploinsufficient in this group of syndromes (Yamagishi et al. 1999). UFD1L is downstream of dHAND, a gene known to be involved in control of the development of structures affected in DGS, and Ufd1l is expressed in the branchial arches, frontonasal mass, and outflow tract. In addition, a single patient has been reported with a de novo deletion affecting UFD1L and the neighboring gene, CDC45L2 (Yamagishi et al. 1999). CDC45 is required for initiation of DNA replication in yeast, and CDC45 mutants are nonviable. However, CDC45L2 expression is not altered in d-HAND Ϫ/Ϫ embryos. On the basis of these findings, Yamagishi and colleagues concluded that UFD1L hap-conditions can be obtained at the e-mail addresses that follow:
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