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  1. Aarskog-Scott syndrome, or faciogenital dysplasia (FGDY), is an inherited disorder characterized by a distinguishing set of craniofacial and skeletal anomalies, disproportionate short stature, and urogenital malformations.

  2. X-linked recessive and autosomal dominant inheritance patterns have been described in FGDY, indicating the presence of genetic heterogeneity. Linkage mapping and positional cloning efforts in the proximal short arm of the X chromosome (Xp11.21) led to the isolation of the gene involved in the X-linked Aarskog-Scott syndrome (FGD1).

  3. In addition to a chromosomal translocation breakpoint, two different single-base insertional frameshift mutations in the FGD1 gene have been identified in patients with familial Aarskog-Scott syndrome.

  4. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates Cdc42, a member of the Rho (Ras homology) family of the p21 GTPases. By activating Cdc42, FGD1 protein stimulates fibroblasts to form filopodia, cytoskeletal elements involved in cellular signaling, adhesion, and migration. Through Cdc42, FGD1 protein also activates the c-Jun N-terminal kinase (JNK) signaling cascade, a pathway that regulates cell growth, apoptosis, and cellular differentiation.

  5. FGD1 contains additional motifs commonly associated with signaling proteins, including a pleckstrin homology (PH) domain, an evolutionarily conserved phosphatidylinositol-3-phosphate-binding FYVE domain, and two potential Src-homology 3 (SH3) binding sites. These additional domains may function to regulate the activity and/or location of the FGD1 protein.

  6. Within the developing mouse skeleton, FGD1 protein is expressed in precartilaginous mesenchymal condensations, the perichondrium and periostium, proliferating chondrocytes, and osteoblasts. These results suggest that FGD1 signaling may play a role in the biology of several different skeletal cell types including mesenchymal prechondrocytes, chondrocytes, and osteoblasts. The characterization of the spatiotemporal pattern of FGD1 expression in mouse embryos has provided important clues to the understanding of the pathogenesis of Aarskog-Scott syndrome.

  7. It appears likely that the primary defect in Aarskog-Scott syndrome is an abnormality of FGD1/Cdc42 signaling resulting in anomalous embryonic development and abnormal endochondral and intramembranous bone formation.

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