Phenotypic heterogeneity in AAAS gene mutation

Barat, P.; Goizet, Cyril; Tullio-Pelet, Anna; Puel, Olivia; Labessan, C.; Barthélémy, Anne

doi:10.1111/j.1651-2227.2004.tb02760.x

Cited by 14 publications

(8 citation statements)

References 7 publications

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“…Given the high correlation between markers across this region, we cannot unequivocally localize the association signal to any one gene. For example, one of the SNPs rs4759021 lies in the AAAS gene, which has been implicated in ‘Triple A Syndrome’, in which osteopenia occasionally occurs ( 17 , 18 ). We also note that our association signal is very strong around the candidate gene Osterix .…”

Section: Discussionmentioning

confidence: 99%

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Timpson

Tobias

Richards

et al. 2009

Human Molecular Genetics

121

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Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10−4; Australia: P = 3.7 × 10−4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10−11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10−5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

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Section: Discussionmentioning

confidence: 99%

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Timpson

Tobias

Richards

et al. 2009

Human Molecular Genetics

121

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“…Palmar and plantar keratosis is a frequent dermatologic manifestation. Mutations in the AAAS gene on 12q13, which codes for a 546 amino acid protein called ALADIN (for alacrima–achalasia–adrenal insufficiency neurologic disorder), have been described in several individuals (Table 1) (5–7, 10–12, 14–25).…”

Section: List Of Reported Mutations In Patients With Aaas To Datementioning

confidence: 99%

Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005

Brooks¹,

Kleta²,

Stuart³

et al. 2005

Clinical Genetics

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Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

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“…Homozygous and compound heterozygous mutations in the AAAS gene have been identified in a number of families affected by triple A syndrome [4]. Studies conducted so far have not established significant genotype-phenotype relationship [2].…”

Section: Introductionmentioning

confidence: 99%

Triple A syndrome: 32 years experience of a single centre (1977–2008)

et al. 2010

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Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977-2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype-phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.

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Phenotypic heterogeneity in AAAS gene mutation

Cited by 14 publications

References 7 publications

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000–2005

Triple A syndrome: 32 years experience of a single centre (1977–2008)

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