Simpson-Golabi-Behmel syndrome: Genotype/phenotype analysis of 18 affected males from 7 unrelated families

Abstract

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth disorder recently shown to be caused by mutations in the heparan sulfate proteoglycan GPC3 [Pilia et al., Nat Genet; 12:241-247 1996]. We have used Southern blot analysis and polymerase chain reaction amplification of intra-exonic sequences to identify four new GPC3 mutations and further characterize three previously reported SGBS mutations. De novo GPC3 mutations were identified in 2 families. In general, the mutations were unique deletions ranging from less than 0.1 kb to more than 300 kb in length with no evidence of a mutational hot spot discerned. The lack of correlation between the phenotype of 18 affected males from these 7 families and the location and size of the GPC3 gene mutations suggest that SGBS is caused by a nonfunctional GPC3 protein.

Glypicans: proteoglycans with a surprise

“…Most of the GPC3 mutations identified so far are point mutations or small deletions encompassing a varying number of exons (31)(32)(33)(34). Given the lack of correlation between patient phenotype and the location of the mutations, it has been proposed that SGBS is caused by the lack of a functional GPC3 protein, with additional genetic factors being responsible for the intra-and interfamilial phenotypic variation (31).…”

“…Given the lack of correlation between patient phenotype and the location of the mutations, it has been proposed that SGBS is caused by the lack of a functional GPC3 protein, with additional genetic factors being responsible for the intra-and interfamilial phenotypic variation (31). The generation of GPC3-deficient mice has provided a strong support to this hypothesis (35).…”

Glypican-3 expression is silenced in human breast cancer

“…This is an X-linked condition characterized by pre-and postnatal overgrowth, and a broad spectrum of clinical manifestations that vary from a mild phenotype in carrier females to infantile lethal forms in some males (Behmel et al, 1984;Garganta et al, 1992;Golabi et al, 1984;Neri et al, 1998). The list of abnormalities observed in SGBS patients can include a distinct facial appearance, and malformations involving craniofacial development (macroglossia, cleft lip/palate, dental malocclusion), chest/skeleton (polydactyly, syndactyly, supernumerary nipples, supernumerary ribs), genitalia (hypospadias, cryptorchidism), and internal organs (cardiac defects, diaphragmatic hernias, renal cystic dysplasia) (Garganta et al, 1992;Hughes-Benzie et al, 1996;Neri et al, 1998). An increased risk for the development of pediatric tumors has also been reported (HughesBenzie et al, 1992).…”

Signalling Mechanisms Underlying Congenital Malformation: The Gatekeepers, Glypicans

“…Since then, different Gpc-3 mutations have been identified in patients and these were found to be rather heterogeneous ranging from large chromosomal rearrangements to micro deletions and point mutations in different exons (Gurrieri et al , 2011;Hughes-Benzie et al, 1996;Pilia et al, 1996;Sakazume et al, 2007;Xuan et al, 1999). Sequence analysis of mutated loci, led to the proposal that SimpsonGolabi-Behmel Syndrome is caused by a non-functional GPC-3 protein while additional unknown genetic factors were possibly responsible for the phenotypic variations among patients.…”