Ciliopathy: Alström Syndrome

Tsang, Stephen H.; Aycinena, Alicia R. P.; Sharma, Tarun

doi:10.1007/978-3-319-95046-4_35

Cited by 22 publications

(18 citation statements)

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“…Most AS clinical manifestations appear during the first few years of birth, although few of them appear later in life. In general AS is diagnosed on the basis of clinical manifestations, medical history and positive family history (Tsang et al, 2018). However, variable expressivity of the disease and age of onset makes the clinical diagnosis a challenging task.…”

Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Kamal

Sahly

Banaganapalli

et al. 2020

Saudi Journal of Biological Sciences

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Alström syndrome (AS, OMIM ID 203800) is a rare childhood multiorgan disorder, which is widely studied in non-Arab ethnic patients. The clinical and molecular basis of AS and the mode of disease inheritance in consanguineous Arab populations is not well investigated. Therefore, to identify the molecular basis of AS in familial forms, the present study performed whole exome sequencing of 5 AS patients belonging to 2 different Bedouin families from Saudi Arabia. The present study identified the AS causative rare biallelic mutations in ALMS gene:T376S in exon 5 and S909* in exon 8 for family A and an R2721* in exon 10 (R2721*) for family B. ALMS1 targeted genetic sequencing of healthy population controls and family members has confirmed its extremely rare frequency and autosomal recessive mode of inheritance. The truncating mutations S909* and R2721* could cause the loss of CC domains and ALMS motif on C-terminal end of the protein and creates unstable protein, which eventually undergoes intracellular degradation. The premature protein truncating mutations described in our study may eventually provide further insight into the functional domains of the ALMS1 protein and contribute to the understanding of the phenotypic spectrum of AS. Whole exome sequencing based molecular diagnosis is expected to rule out ambiguity surrounding clinical diagnosis of suspected AS cases.

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Section: Introductionmentioning

confidence: 99%

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Kamal

Sahly

Banaganapalli

et al. 2020

Saudi Journal of Biological Sciences

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“…Several lines of evidence have documented a connection between primary cilia and obesity 24 . Human genetic ciliopathy such as Bardet-Biedl syndrome and Alström's syndrome manifests obesity and type 2 diabetes 25,26 . Generalized ciliary dysgenesis in adult mice leads to hyperphagic obesity 27 .…”

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confidence: 99%

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

et al. 2020

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Hypothalamic neurons including proopiomelanocortin (POMC)-producing neurons regulate body weights. The non-motile primary cilium is a critical sensory organelle on the cell surface. An association between ciliary defects and obesity has been suggested, but the underlying mechanisms are not fully understood. Here we show that inhibition of ciliogenesis in POMC-expressing developing hypothalamic neurons, by depleting ciliogenic genes IFT88 and KIF3A, leads to adulthood obesity in mice. In contrast, adult-onset ciliary dysgenesis in POMC neurons causes no significant change in adiposity. In developing POMC neurons, abnormal cilia formation disrupts axonal projections through impaired lysosomal protein degradation. Notably, maternal nutrition and postnatal leptin surge have a profound impact on ciliogenesis in the hypothalamus of neonatal mice; through these effects they critically modulate the organization of hypothalamic feeding circuits. Our findings reveal a mechanism of early life programming of adult adiposity, which is mediated by primary cilia in developing hypothalamic neurons.

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“…7 The list of confirmed ciliopathies is constantly expanding and currently includes disorders such as Alström syndrome (MIM: 203800), Bardet ), and others (see ''GeneReviews'' in web resources). [8][9][10][11][12][13][14][15] Much of the pathology of the ciliopathy syndromes can be attributed to the adverse effects of ciliary dysfunction on cell signaling pathways critical to embryologic development. 7,16 Furthermore, although each ciliopathy is defined by its own unique constellation of characteristic phenotypic findings, many ciliopathies share similar or overlapping features.…”

Section: Introductionmentioning

confidence: 99%

Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis

Drivas

Lucas

Zhang

et al. 2021

The American Journal of Human Genetics

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Rare monogenic disorders of the primary cilium, termed ciliopathies, are characterized by extreme presentations of otherwise common diseases, such as diabetes, hepatic fibrosis, and kidney failure. However, despite a recent revolution in our understanding of the cilium's role in rare disease pathogenesis, the organelle's contribution to common disease remains largely unknown. Hypothesizing that common genetic variants within Mendelian ciliopathy genes might contribute to common complex diseases pathogenesis, we performed association studies of 16,874 common genetic variants across 122 ciliary genes with 12 quantitative laboratory traits characteristic of ciliopathy syndromes in 452,593 individuals in the UK Biobank. We incorporated tissue-specific gene expression analysis, expression quantitative trait loci, and Mendelian disease phenotype information into our analysis and replicated our findings in meta-analysis. 101 statistically significant associations were identified across 42 of the 122 examined ciliary genes (including eight novel replicating associations). These ciliary genes were widely expressed in tissues relevant to the phenotypes being studied, and eQTL analysis revealed strong evidence for correlation between ciliary gene expression levels and laboratory traits. Perhaps most interestingly, our analysis identified different ciliary subcompartments as being specifically associated with distinct sets of phenotypes. Taken together, our data demonstrate the utility of a Mendelian pathwaybased approach to genomic association studies, challenge the widely held belief that the cilium is an organelle important mainly in development and in rare syndromic disease pathogenesis, and provide a framework for the continued integration of common and rare disease genetics to provide insight into the pathophysiology of human diseases of immense public health burden.

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Ciliopathy: Alström Syndrome

Cited by 22 publications

References 1 publication

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

Primary cilia mediate early life programming of adiposity through lysosomal regulation in the developing mouse hypothalamus

Mendelian pathway analysis of laboratory traits reveals distinct roles for ciliary subcompartments in common disease pathogenesis

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