Dental findings in patients with Aarskog syndrome

Halse, Agnar; Bjorvatn, Kjell; Aarskog, Dagfinn

doi:10.1111/j.1600-0722.1979.tb00679.x

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…In 1970, Aarskog described an X-linked recessive syndrome characterized by an upturned nose, short stature, multiple dental defects, delayed skeletal age, and multiple bone malformations (1,2). Later work confirmed these observations, naming the disorder faciogenital dysplasia (FGDY) or Aarskog-Scott syndrome and identified the gene mutated as FYVE, RhoGEF, and PH domain-containing 1 (FGD1) (3).…”

Section: Introductionsupporting

confidence: 50%

MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

Zou¹,

Greenblatt²,

Shim³

et al. 2011

J. Clin. Invest.

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Mutations in human FYVE, RhoGEF, and PH domain-containing 1 (FGD1) cause faciogenital dysplasia (FGDY; also known as Aarskog syndrome), an X-linked disorder that affects multiple skeletal structures. FGD1 encodes a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase CDC42. However, the mechanisms by which mutations in FGD1 affect skeletal development are unknown. Here, we describe what we believe to be a novel signaling pathway in osteoblasts initiated by FGD1 that involves the MAP3K mixed-lineage kinase 3 (MLK3). We observed that MLK3 functions downstream of FGD1 to regulate ERK and p38 MAPK, which in turn phosphorylate and activate the master regulator of osteoblast differentiation, Runx2. Mutations in FGD1 found in individuals with FGDY ablated its ability to activate MLK3. Consistent with our description of this pathway and the phenotype of patients with FGD1 mutations, mice with a targeted deletion of Mlk3 displayed multiple skeletal defects, including dental abnormalities, deficient calvarial mineralization, and reduced bone mass. Furthermore, mice with knockin of a mutant Mlk3 allele that is resistant to activation by FGD1/CDC42 displayed similar skeletal defects, demonstrating that activation of MLK3 specifically by FGD1/CDC42 is important for skeletal mineralization. Thus, our results provide a putative biochemical mechanism for the skeletal defects in human FGDY and suggest that modulating MAPK signaling may benefit these patients. IntroductionIn 1970, Aarskog described an X-linked recessive syndrome characterized by an upturned nose, short stature, multiple dental defects, delayed skeletal age, and multiple bone malformations (1, 2). Later work confirmed these observations, naming the disorder faciogenital dysplasia (FGDY) or Aarskog-Scott syndrome and identified the gene mutated as FYVE, RhoGEF, and PH domain-containing 1 (FGD1) (3). FGD1 encodes a member of the guanine nucleotide exchange factor (GEF) family, which catalyses the exchange of GDP for GTP and promotes the activity of Rho family GTPases (3-6). More than 16 distinct FGD1 mutations have been reported to cosegregate with FGDY. These mutations include deletions and premature truncations, implying that a loss of FGD1 function underlies FGDY (6, 7). Despite these insights into the genetic basis of FGDY, it remains unclear how FGD1 affects bone development.Expression analysis demonstrates that FGD1 is highly expressed in osteoblasts, suggesting that FGD1 signaling plays a critical role in osteoblast differentiation and function (8). Microinjection studies show that FGD1 specifically activates CDC42, a member of the Rho (Ras homology) family of GTPase proteins (4, 5). A

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Section: Introductionsupporting

confidence: 50%

MLK3 regulates bone development downstream of the faciogenital dysplasia protein FGD1 in mice

Zou¹,

Greenblatt²,

Shim³

et al. 2011

J. Clin. Invest.

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“…A number of conditions have been shown to be associated with deviations in dental and skeletal maturity. Dental age is reported to be delayed in cleft lip/palate patients (1,2), children with chronic renal failure (3), cystic ®brosis (4), and patients with hepatorenal glycogen storage disease (5) and Aarskog syndrome (6). Dental maturity is generally retarded in patients with hypopituitarism, although less regularly and to a lesser degree than skeletal or statural growth (7).…”

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confidence: 99%

Advanced dental maturity in children with juvenile rheumatoid arthritis

Lehtinen

Oksa

Helenius

et al. 2000

European J Oral Sciences

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The subjects of the investigation comprised 95 girls and 73 boys with juvenile rheumatoid arthritis (JRA), and 102 girls and 66 boys representing healthy controls, all with a chronological age from 6.3 to 14.4 yr. The dental development was assessed from panoramic radiographs using a seven-tooth model. The radiographs were evaluated on three separate occasions with a minimum interval of one month in a randomized order, and blind with respect to absence or presence of JRA. In both JRA patients and healthy controls, dental maturity was ahead of chronological age. In addition, dental maturity was significantly advanced in JRA patients with 0.26 yr in girls and 0.28 yr in boys. It is tentatively suggested that the advanced dental development in JRA patients compared with healthy children was partly an effect of treatment with cortisone, while the influence of the disorder per se remains to be elucidated.

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