Molecular Genetics of Simpson‐Golabi‐Behmel Syndrome Type 1

Abstract

Simpson‐Golabi‐Behmel syndrome (SGBS; OMIM #312870) is a recessive X‐linked overgrowth disorder manifesting multiple congenital anomalies and visceral and skeletal abnormalities. It is caused by deletions or duplications of the heparan sulfate proteoglycan glypican 3‐gene (GPC3; OMIM #30037) and/or duplication of the glypican 4‐gene (GPC4; OMIM #300168) at Xq26. Heparan sulfate proteoglycans mechanism of GPC3 and GPC4 in producing the SGBS phenotype is poorly understood and SGBS is suspected to be under‐reported. Suspected SGBS individuals should be tested for GPC3 mutations or deletion and GPC4 duplication. Current literature states no correlation between deletion size and phenotype for SGBS. Future investigative studies are recommended to define genotype–phenotype correlation and understand the GPC3/GPC4 gene‐product mechanism.

Key Concepts:

  • GPC3 and GPC4 lay tandem in sequence within the Xq26 locus.

  • The glypican‐3 protein mediates embryonic and cell‐specific tissue formation and development by regulating growth factors.

  • Point mutations or microdeletions in GPC3 or duplication of GPC4 result in a premature termination codon and will be translated to a truncated protein or nonfunctional glypican‐3 or glypican‐4 protein.

  • Loss‐of‐function mutation in GPC3 is associated with SGBS but further studies on GPC4 are necessary to define its association with SGBS.

  • Current literature states no correlation between deletion size and phenotype for SGBS.

Keywords: SGBS; GPC3; GPC4; overgrowth syndrome; multiple congenital anomalies; X‐linked

Figure 1.

A comparison of six mammalian glypican members. Reproduced from Song and Filmus . Copyright by Elsevier.

Figure 2.

The cDNA and protein structure of the GPC3 gene and coding region. Reproduced from Hughes‐Benzie et al. .

Figure 3.

The mutations identified in GPC3 from various sources. Reproduced from Veugelers et al. . Copyright by Oxford University Press.

close

References

Behmel A, Plochl E and Rosenkranz W (1984) A new X‐linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syndrome? Human Genetics 67: 409–413.

Brzustowicz LM, Farrell S, Khan MB and Weksberg R (1999) Mapping of a new SGBS locus to chromosome Xp22 in a family with a severe form of Simpson‐Golabi‐Behmel syndrome. American Journal of Human Genetics 65: 779–783.

Golabi M and Rosen L (1984) A new X‐linked mental retardation‐overgrowth syndrome. American Journal of Medical Genetics 17: 345–358.

Huber R, Mazzarella R and Chen CN (1998) Glypican 3 and glypican 4 are juxtaposed in Xq26.1. Gene 225: 9–16.

Hughes‐Benzie RM, Pilia G, Xuan JY et al. (1996) Simpson‐Golabi‐Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families. American Journal of Medical Genetics 66: 227–234.

Lapunzina P (2005) Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 137C: 53–71.

Neri G, Gurrieri F, Ginevra Z and Lin A (1998) Clinical and molecular aspects of the Simpson‐Golabi‐Behmel Syndrome. American Journal of Medical Genetics 79: 279–283.

Orth U, Gurrieri F, Behmel A et al. (1994) Gene for Simpson‐Golabi‐Behmel syndrome is linked to HPRT in Xq26 in two European families. American Journal of Medical Genetics 50: 338–390.

Paine‐Saunders S, Viviano BL, Zupicich J, Skarnes WC and Saunders S (2000) Glypican‐3 controls cellular responses to Bmp4 in limb patterning and skeletal development. Developmental Biology 255: 179–187.

Pilia G, Hughes‐Benzie RM, MacKenzie A et al. (1996) Mutations in GPC3, a glypican gene, cause the Simpson‐Golabi‐Behmel overgrowth syndrome. Nature Genetics 12: 241–247.

Ratbi I, Elalaoui SC, Moizard MP, Raynaud M and Sefiani A (2010) Novel nonsense mutation of GPC3 gene in a patient with Simpson‐Golabi‐Behmel syndrome. Turkish Journal of Pediatrics 52: 525–528.

Simpson JL, Landey S, New M and German J (1975) A previously unrecognized X‐linked syndrome of dysmorphia. Birth Defects Original Article Series 11: 18–24.

Song H and Filmus J (2002) The role of glypicans in mammalian development. Biochemica et Biophysica Acta 1573: 241–246.

Veugelers M, Cat BD, Muyldermans SY et al. (2000) Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson‐Golabi‐Behmel syndrome: identification of loss‐of‐function mutations in the GPC3 gene. Human Molecular Genetics 9: 1321–1328.

Veugelers M, Vermeesch J, Watanabe K et al. (1998) GPC4, the gene for human K‐glypican, flanks GPC3 on xq26: deletion of the GPC3‐GPC4 gene cluster in one family with Simpson‐Golabi‐Behmel syndrome. Genomics 53: 1–11.

Waterson J, Stockley TL, Segal S and Golabi M (2010) Novel duplication in glypican‐4 as an apparent cause of Simpson‐Golabi‐Behmel syndrome. American Journal of Medical Genetics Part A 152A: 3179–3181.

Weichert J, Schroer A, Amari F et al. (2011) A 1 Mb‐sized microdelection Xq26.2 encompassing the GPC3 gene in a fetus with Simpson‐Golabi‐Behmel syndrome report, antenatal findings and review. European Journal of Medical Genetics 24: 343–347.

Xuan J, Hughes‐Benzie R and MacKenzie A (1999) A small interstitial deletion in the GPC3 gene causes Simpson‐Golabi‐Behmel syndrome in a Dutch‐Canadian family. Journal of Medical Genetics 36(1): 57–58.

Yano S, Baskin B, Bagheri A et al. (2011) Familial Simpson‐Golabi‐Behmel syndrome: studies of X‐chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations. Clinical Genetics 80(5): 466–471.

Further Reading

David G (1993) Integral membrane heparan sulfate proteoglycans. FASEB Journal 7: 1023–1030.

Eggenschwiler J, Ludwig T, Fisher P et al. (1997) Mouse mutant embryos overexpressing IGF‐II exhibit phenotypic features of the Beckwith‐Wiedemann and Simpson‐Golabi‐Behmel syndromes. Genes & Development 11(23): 3128–3142.

Gertsch E, Kirmani S, Ackerman MJ and Babovic‐Vuksanovic D (2010) Transient QT interval prolongation in an infant with Simpson‐Golabi‐Behmel syndrome. American Journal of Medical Genetics 152A: 2379–2382.

Golabi M, Leung A and Lopez C (2011) Simpson‐Golabi‐Behmel Syndrome Type 1. Genereviews [Internet]. Seattle, WA: University of Washington.

Li M, Shuman C, Fei Y et al. (2001) GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson‐Golabi‐Behmel syndrome. American Journal of Medical Genetics 102: 161–168.

Lindsay S, Ireland M, O'Brien O et al. (1997) Large scale deletions in the GPC3 gene may account for minority of cases of Simpson‐Golabi‐Behmel syndrome. Journal of Medical Genetics 34(6): 480–483.

Sakazume S, Okamoto N, Yamamoto T et al. (2007) GPC3 mutations in seven patients with Simpson‐Golabi‐Behmel Syndrome. American Journal of Medical Genetics Part A 143A: 1703–1707.

Verloes A, Massart B, Dehalleux I, Langhendries JP and Koulischer L (1995) Clinical overlap of Beckwith‐Wiedemann, Perlman and Simpson‐Golabi‐Behmel syndromes: a diagnostic pitfall. Clinical Genetics 47(5): 257–262.

Young EL, Wishnow R and Nigro MA (2006) Expanding the clinical picture of Simpson‐Golabi‐Behmel syndrome. Pediatric Neurology 34(2): 139–142.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Golabi, Mahin, and Leung, Alva(Nov 2012) Molecular Genetics of Simpson‐Golabi‐Behmel Syndrome Type 1. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024349]