Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis.

The filamins are cytoplasmic proteins that regulate the structure and activity of the cytoskeleton by cross-linking actin into three-dimensional networks, linking the cell membrane to the cytoskeleton and serving as scaffolds on which intracellular signaling and protein trafficking pathways are organized (reviewed in refs. 1,2). We identified mutations in the gene encoding filamin B in four human skeletal disorders. We found homozygosity or compound heterozygosity with respect to stop-codon mutations in autosomal recessive spondylocarpotarsal syndrome (SCT, OMIM 272460) and missense mutations in individuals with autosomal dominant Larsen syndrome (OMIM 150250) and the perinatal lethal atelosteogenesis I and III phenotypes (AOI, OMIM 108720; AOIII, OMIM 108721). We found that filamin B is expressed in human growth plate chondrocytes and in the developing vertebral bodies in the mouse. These data indicate an unexpected role in vertebral segmentation, joint formation and endochondral ossification for this ubiquitously expressed cytoskeletal protein.

Isolation of a new member of the ADP-ribosylation like factor gene family, ARL8, from a cartilage cDNA library.

ADP-ribosylation factors (ARFs) and ARF-like proteins (ARLs) are part of the ARF family within the RAS superfamily of regulatory GTPases. Guanine nucleotide binding proteins or GTPases are involved in a diverse spectrum of cellular activities, including regulating cell growth and signal transduction, organization of the cytoskeleton and regulating membrane trafficking along the exocytic and endocytic pathways. ARL proteins share 40-60% sequence identity with the ARF proteins, but ARLs can be distinguished from ARFs based on expression patterns and biological functions. We have identified a new ARL, ARL8, from a fetal cartilage cDNA library. ARL8 contains six exons and five introns, and encodes a 179 amino acid protein that shares homology to the other ARL proteins, especially ARL5. It also shows significant homology with orthologous proteins found in Mus musculus and Drosophila melanogaster. The expression pattern of the mouse ortholog revealed differential tissue expression and an alternate transcript was seen in brain that was age-dependent. ARL8 is an additional member of a family of closely related proteins that are conserved both within the family and across species.

Evidence that Smith-McCort dysplasia and Dyggve-Melchior-Clausen dysplasia are allelic disorders that result from mutations in a gene on chromosome 18q12.

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and a short trunk with a barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. We performed a genomewide scan in a consanguineous family from Guam and found evidence of linkage to loci on chromosome 18q12. Analysis of a second, smaller family was also consistent with linkage to this region, producing a maximum combined two-point LOD score of 3.04 at a recombination fraction of 0 for the marker at locus D18S450. A 10.7-cM region containing the disease gene was defined by recombination events in two affected individuals in the larger family. Furthermore, all affected children in the larger family were homozygous for a subset of marker loci within this region, defining a 1.5-cM interval likely to contain the defective gene. Analysis of three small, unrelated families with Dyggve-Melchior-Clausen syndrome, a radiographically identical disorder with the additional clinical finding of mental retardation, provided evidence of linkage to the same region, a result consistent with the hypothesis that the two disorders are allelic.