Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: A putative RhoRac guanine nucleotide exchange factor

Pasteris, N. German; Cadle, A. B.; Logie, L. J.; Porteous, Mary; Schwartz, Charles E.; Stevenson, Roger E.; Glover, Thomas W.; Wilroy, R. Sid; Gorski, Jerome L.

doi:10.1016/0092-8674(94)90552-5

Cited by 272 publications

(29 citation statements)

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“…130 ASS is an X-linked recessive developmental disorder characterized by short stature, by facial, skeletal, and urogenital anomalies, and by mild mental retardation. The ASS-associated FGD1 mutations cause loss-of-function (deletion, nonsense mutations causing expression of truncated proteins, missense mutations in DH-PH domains) and account for ~20% of individuals with ASS.…”

Section: Rhogefs and Other Human Diseasesmentioning

confidence: 99%

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Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

2013

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The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly by indirect mechanisms in disease. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflect the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2, Tiam1, Vav and P-Rex1/2.

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Section: Rhogefs and Other Human Diseasesmentioning

confidence: 99%

“…The ASS-associated FGD1 mutations cause loss-of-function (deletion, nonsense mutations causing expression of truncated proteins, missense mutations in DH-PH domains) and account for ~20% of individuals with ASS. 130,131 …”

Section: Rhogefs and Other Human Diseasesmentioning

confidence: 99%

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

2013

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“…The intracellular defects are highly heterogeneous, such as RAS (rat sarcoma)-MAPK (mitogen-activated protein kinase) pathway [9–20], guanine nucleotide exchange factor [21–23], cyclic AMP (cAMP) dependent regulatory subunit of protein kinase A [24], and other signaling proteins [25–32]. Especially, altered RAS-MAPK signaling has been identified as a key pathway in regulation of growth plate chondrogenesis and is affected in several disorders, referred to as RASopathies [33].…”

Section: Genetics Of Short Staturementioning

confidence: 99%

Genetics of Short Stature

Jee¹,

Andrade

Baron³

et al. 2017

Endocrinology and Metabolism Clinics of North America

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Synopsis Short stature is a common and heterogeneous condition which is often genetic in etiology. For most children with genetic short stature, the specific molecular causes remain unknown, but with advances in exome/genome sequencing and bioinformatics approaches, new genetic causes of growth disorders have been identified, contributing to the understanding of the underlying molecular mechanisms of longitudinal bone growth and growth failure. These genetic causes can involve not only hormonal deficiencies, including the growth hormone-IGF-1 axis, thyroid hormone or glucocorticoid and defects in hormonal receptors or subsequent signaling, but also defects in fundamental cellular processes (intracellular signaling pathways, transcriptional regulation, and DNA repair), extracellular matrix, or paracrine signaling. Especially, heterozygous and/or mild mutations in SHOX, NPR2, ACAN, IGF1, IGF1R, or FGFR3 have been associated with isolated short stature without other prominent or noticeable phenotype while homozygous and/or severe mutations in these genes cause severe short stature with bone malformation, that is, a chondrodysplasia. Identifying new genetic causes of growth disorders has the potential to improve diagnosis, prognostic accuracy, individualized management, and help avoid unnecessary testing for endocrine and other disorders.

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“…Genetic aberrations in several other intracellular pathways play a role in short stature syndromes. For example, mutations in FGD1, encoding a guanine nucleotide exchange factor of the Rho/Rac family of small GTP-binding proteins, cause the X-linked form of Aarskog-Scott syndrome (faciogenital dysplasia) (161), although in only 18% of clinically suspected cases a mutation was found (162). FGD1 activates MAP3K mixedlineage kinase 3 (MLK3), which regulates ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, RUNX2 (163).…”

Section: Genetic Defects Of Intracellular Pathwaysmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

Wit

Oostdijk

Losekoot

et al. 2016

European Journal of Endocrinology

150

132

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The fast technological development, particularly single nucleotide polymorphism array, array-comparative genomic hybridization, and whole exome sequencing, has led to the discovery of many novel genetic causes of growth failure. In this review we discuss a selection of these, according to a diagnostic classification centred on the epiphyseal growth plate. We successively discuss disorders in hormone signalling, paracrine factors, matrix molecules, intracellular pathways, and fundamental cellular processes, followed by chromosomal aberrations including copy number variants (CNVs) and imprinting disorders associated with short stature. Many novel causes of GH deficiency (GHD) as part of combined pituitary hormone deficiency have been uncovered. The most frequent genetic causes of isolated GHD are GH1 and GHRHR defects, but several novel causes have recently been found, such as GHSR, RNPC3, and IFT172 mutations. Besides well-defined causes of GH insensitivity (GHR, STAT5B, IGFALS, IGF1 defects), disorders of NFkB signalling, STAT3 and IGF2 have recently been discovered. Heterozygous IGF1R defects are a relatively frequent cause of prenatal and postnatal growth retardation. TRHA mutations cause a syndromic form of short stature with elevated T 3 /T 4 ratio. Disorders of signalling of various paracrine factors (FGFs, BMPs, WNTs, PTHrP/IHH, and CNP/NPR2) or genetic defects affecting cartilage extracellular matrix usually cause disproportionate short stature. Heterozygous NPR2 or SHOX defects may be found in w3% of short children, and also rasopathies (e.g., Noonan syndrome) can be found in children without clear syndromic appearance. Numerous other syndromes associated with short stature are caused by genetic defects in fundamental cellular processes, chromosomal abnormalities, CNVs, and imprinting disorders.

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Isolation and characterization of the faciogenital dysplasia (Aarskog-Scott syndrome) gene: A putative RhoRac guanine nucleotide exchange factor

Cited by 272 publications

References 50 publications

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

Genetics of Short Stature

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

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