ABSTRACT
SATB2-associated syndrome (SAS) is a rare disorder caused by alterations in the special AT-rich sequence-binding protein 2 (SATB2). Skeletal abnormalities such as tibial bowing, osteomalacia, osteopenia or osteoporosis have been reported suggesting a higher frequency of skeletal complications in SAS. The optimal timing, necessity, and methodology for routine assessment of bone health in individuals with SAS, however, remain unclear. We report molecular and phenotypic features of 7 individuals with SAS documented to have low bone mineral density (BMD) ascertained by dual-energy X-ray absorptiometry (DXA), often preceded by tibial bowing. The lowest BMD Z-scores ranged -2.3 to -5.6. In 4 individuals, total alkaline phosphatase levels were elevated (2 with elevated bone fraction) around the time of low BMD documentation. A clinically significant fracture history and a diagnosis of pediatric osteoporosis were present in 4 individuals. Pamidronate treatment in 2 children improved BMD. In conclusion, low BMD, fractures, and tibial bowing are relatively common skeletal complications in individuals with SAS. DXA is a useful tool when evaluating a child with SAS suspected to have low BMD and the results might alter clinical management.
Subject(s)
Bone Development/genetics , Bone Diseases, Developmental/diagnosis , Bone Diseases, Developmental/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/genetics , Adolescent , Bone Density , Bone and Bones/diagnostic imaging , Bone and Bones/metabolism , Child , Child, Preschool , Female , Humans , Male , Phenotype , Radiography , SyndromeABSTRACT
SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.
Subject(s)
Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Intellectual Disability/genetics , Matrix Attachment Region Binding Proteins/genetics , Transcription Factors/genetics , Adolescent , Child , Child, Preschool , Craniofacial Abnormalities/physiopathology , Developmental Disabilities/physiopathology , Exome/genetics , Female , Frameshift Mutation , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Infant , Intellectual Disability/physiopathology , Male , PhenotypeABSTRACT
A cDNA encoding the human spermidine/spermine N1-acetyltransferase (N1SSAT) was conditionally expressed in a strain of Escherichia coli deficient in spermidine-acetylating activity. Conditional expression of this cDNA was performed under the control of the lac promoter, by addition of the non-hydrolysable lactose analogue isopropyl beta-D-thiogalactoside. Expression of the N1SSAT cDNA oriented in the sense direction resulted in the acetylation of spermidine at the N1 but not the N8 position and a decrease in endogenous spermidine contents and growth rates in these bacteria. When this cDNA was expressed in the antisense orientation, spermidine acetylation was not detected and endogenous spermidine contents and growth rates were unaffected. Increasing the endogenous N1-acetylspermidine concentration by addition of this amine to the culture medium did not suppress growth, and increasing endogenous spermidine pools by exogenous addition was not sufficient to restore optimal growth in cells expressing the human N1SSAT. Exogenous spermidine, but neither N1- nor N8-acetylspermidine, stimulated cell growth in strains unable to synthesize spermidine. These results suggest that one physiological consequence of spermidine acetylation in E. coli is growth inhibition. The mechanism of this inhibition seems to involve the formation of acetylspermidine, and is not simply due to a decrease in the intracellular concentration of non-acetylated spermidine.
