Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.
Opitz syndrome (OS) is an inherited disorder characterized by midline defects including hypertelorism, hypospadias, lip-palate-laryngotracheal clefts and imperforate anus. We have identified a new gene on Xp22, MiD1 (Midline 1), which is disrupted in an OS patient carrying an X-chromosome inversion and is also mutated in several OS families.MIDI encodes a member of the B-box family of proteins, which contain protein-protein interaction domains, including a RING finger, and are implicated in fundamental processes such as body axis patterning and control of cell proliferation. The association of MIDI with OS suggests an important role for this gene in midline development
Pfeiffer syndrome (PS) is an autosomal dominant skeletal disorder which affects the bones of the skull, hands and feet. Previously, we have mapped PS in a subset of families to chromosome 8cen by linkage analysis and demonstrated a common mutation in the fibroblast growth factor receptor-1 (FGFR1) gene in the linked families. Here we report a second locus for PS on chromosome 10q25, and present evidence that mutations in the fibroblast growth factor receptor-2 (FGFR2) gene on 10q25 cause PS in an additional subset of familial and sporadic cases. Three different point mutations in FGFR2, which alter the same acceptor splice site of exon B, were observed in both sporadic and familial PS. In addition, a T to C transition in exon B predicting a cysteine to arginine substitution was identified in three sporadic PS individuals. Interestingly, this T to C change is identical to a mutation in FGFR2 previously reported in Crouzon syndrome, a phenotypically similar disorder but one lacking the hand and foot anomalies seen in PS. Our results highlight the genetic heterogeneity in PS and suggest that the molecular data will be an important complement to the clinical phenotype in defining craniosynostosis syndromes.
Opitz syndrome (OS, McKusick 145410) is a well described genetic syndrome affecting multiple organ systems whose cardinal manifestations include widely spaced eyes and hypospadias (Fig. 1). It was first reported as two separate entities, BBB syndrome, and G syndrome. However, subsequent reports of families in which the BBB and G syndrome segregated within a single kindred suggested that they were a single clinical entity. Although the original pedigrees were consistent with X-linked and autosomal dominant inheritance, male-to-male transmission in subsequent reports suggested that OS was inherited as an autosomal dominant trait. Here we report that OS is a heterogeneous disorder, with an X-linked and an autosomal locus. Three families were linked to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. Five families were linked to D22S345 from chromosome 22q11.2, with a lod score of 3.53 at zero recombination. This represents the first classic multiple congenital anomaly syndrome with an X-linked and an autosomal form.
The MID1 gene in Xp22 codes for a novel member of proteins containing a RING finger, B-box, coiled-coil and a conserved C-terminal domain. Initially, three mutations in the C-terminal region were found in patients with Opitz G/BBB syndrome, a defect of midline development. Here we have determined the complete gene structure of the MID1 gene and have analyzed all nine exons for mutations in a set of 40 unrelated Opitz G/BBB patients. We now report six additional mutations all clustered in the carboxy-terminal domain of the MID1 protein. These data suggest that this conserved domain of the B-box proteins may play a fundamental role in the pathogenesis of Opitz syndrome and in morphogenetic events at the midline during blastogenesis.
Fibrodysplasia ossificans progressiva (FOP) is a severely disabling, autosomal-dominant disorder of connective tissue and is characterized by postnatal progressive heterotopic ossification of muscle, tendon, ligament, and fascia and by congenital malformation of the great toes. To identify the chromosomal location of the FOP gene, we conducted a genomewide linkage analysis, using four affected families with a total of 14 informative meioses. Male-to-male transmission of the FOP phenotype excluded X-linked inheritance. Highly polymorphic microsatellite markers covering all human autosomes were amplified by use of PCR. The FOP phenotype is linked to markers located in the 4q27-31 region (LOD score 3.10 at recombination fraction 0). Crossover events localize the putative FOP gene within a 36-cM interval bordered proximally by D4S1625 and distally by D4S2417. This interval contains at least one gene involved in the bone morphogenetic protein-signaling pathway.
Developmental dysplasia of the hip (DDH) is a debilitating condition characterized by incomplete formation of the acetabulum leading to dislocation of the femur, suboptimal joint function, and accelerated wear of the articular cartilage resulting in arthritis. DDH affects 1 in 1000 newborns in the United States; there are well-defined "pockets" of high prevalence in Japan, and in Italy and other Mediterranean countries. Although reasonably accurate for detecting gross forms of hip dysplasia, existing techniques fail to find milder forms of dysplasia. Undetected hip dysplasia is the leading cause of osteoarthritis of the hip in young individuals, causing over 40% of cases in this age group. A sensitive and specific test for DDH has remained a desirable yet elusive goal in orthopedics for a long time. A 72-member, four-generation affected family has been recruited, and DNA from its members retrieved. Genomewide linkage analysis revealed a 2.61-Mb candidate region (38.7-41.31 Mb from the p term of chromosome 3) co-inherited by all affected members with a maximum logarithm (base 10) of odds (LOD) score of 3.31. Whole exome sequencing and analysis of this candidate region in four severely affected family members revealed one shared variant, rs3732378, that causes a threonine (polar) to methionine (non-polar) alteration at position 280 in the transmembrane domain of CX3CR1. This mutation is predicted to have a deleterious effect on its encoded protein, which functions as a receptor for the ligand fractalkine. By Sanger sequencing this variant was found to be present in the DNA of all affected individuals and obligate heterozygotes. CX3CR1 mediates cellular adhesive and migratory functions and is known to be expressed in mesenchymal stem cells destined to become chondrocytes. A genetic risk factor that might be among the etiologic factors for the family in this study has been identified, along with other possible aggravating mutations shared by four severely affected family members. These findings might illuminate the molecular pathways affecting chondrocyte maturation and bone formation.
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