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Frontiers in Endocrinology 2022The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to... (Review)
Review
The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.
Topics: Cilia; Glucagon-Secreting Cells; Insulysin; Pancreatic Hormones; Signal Transduction
PubMed: 35832432
DOI: 10.3389/fendo.2022.922825 -
Diabetes Sep 2022Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic...
Adipose tissue is a key regulator of whole-body metabolic fitness because of its role in controlling insulin sensitivity. Obesity is associated with hypertrophic adipocytes with impaired glucose absorption, a phenomenon existing in the ultrarare monogenic disorder Alström syndrome consisting of severe insulin resistance. Inactivation of ALMS1 directly inhibits insulin-mediated glucose absorption in the white adipose tissue and induces severe insulin resistance, which leads to type 2 diabetes, accelerated nonalcoholic liver disease, and fibrosis. These phenotypes were reversed by specific adipocyte-ALMS1 reactivation in vivo. Subsequently, ALMS1 was found to bind to protein kinase C-α (PKCα) in the adipocyte, and upon insulin signaling, PKCα is released from ALMS1. α-Helices in the kinase domain of PKCα were therefore screened to identify a peptide sequence that interfered with the ALMS1-PKCα protein interaction. When incubated with cultured human adipocytes, the stapled peptide termed PATAS, for Peptide derived of PKC Alpha Targeting AlmS, triggered insulin-independent glucose absorption, de novo lipogenesis, and cellular glucose utilization. In vivo, PATAS reduced whole-body insulin resistance, and improved glucose intolerance, fasting glucose, liver steatosis, and fibrosis in rodents. Thus, PATAS represents a novel first-in-class peptide that targets the adipocyte to ameliorate insulin resistance and its associated comorbidities.
Topics: Alstrom Syndrome; Biological Products; Diabetes Mellitus, Type 2; Fibrosis; Glucose; Humans; Insulin; Insulin Resistance; Protein Kinase C-alpha
PubMed: 35822820
DOI: 10.2337/db22-0058 -
Bone Reports Dec 2022Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of...
OBJECTIVES
Causative variants in genes responsible for Alström syndrome (ALMS) and Bardet-Biedl syndrome (BBS) cause damage to primary cilia associated with correct functioning of cell signaling pathways in many tissues. Despite differences in genetic background, both syndromes affect multiple organs and numerous clinical manifestations are common including obesity, retinal degeneration, insulin resistance, type 2 diabetes and many others. The aim of the study was to evaluate bone metabolism abnormalities and their relation to metabolic disorders based on bone turnover markers and presence of mandibular atrophy in patients with ALMS and BBS syndromes.
MATERIAL AND METHODS
In 18 patients (11 with ALMS and 7 with BBS aged 5-29) and in 42 age-matched ( < 0.05) healthy subjects, the following markers of bone turnover were assessed: serum osteocalcin (OC), osteoprotegerin (OPG), s-RANKL and urinary deoxypyridinoline - DPD. In addition, a severity of alveolar atrophy using dental panoramic radiograms was evaluated.
RESULTS
Lower serum OC ( = 0.0004) and urinary DPD levels ( = 0.0056) were observed in the study group compared to controls. In ALMS and BBS patients, serum OC and urinary DPD values negatively correlated with the HOMA-IR index, while a positive correlation between the OC and 25-OHD levels and a negative correlation between s-RANKL and fasting glucose concentrations were found. A significant difference in the incidence of low-grade mandibular atrophy between patients with ALMS and BBS and controls ( < 0.0001) was observed.
CONCLUSIONS
The identification of bone metabolism disorders in patients with ALMS and BBS syndromes indicates the necessity to provide them with appropriate diagnosis and treatment of these abnormalities.
PubMed: 35818441
DOI: 10.1016/j.bonr.2022.101600 -
Ophthalmic Genetics Aug 2022
Topics: Alstrom Syndrome; Asian People; Cell Cycle Proteins; China; Humans; Mutation
PubMed: 35786123
DOI: 10.1080/13816810.2022.2092759 -
Otology & Neurotology : Official... Jul 2022To characterize the patterns of hearing loss and methods of hearing rehabilitation in the UK national cohort of adults with Alström syndrome.
OBJECTIVE
To characterize the patterns of hearing loss and methods of hearing rehabilitation in the UK national cohort of adults with Alström syndrome.
STUDY DESIGN
Retrospective review of electronic patient records.
SETTING
UK National multi-disciplinary team (MDT) Alström service held at the Queen Elizabeth Hospital, Birmingham.
PATIENTS
Forty one adult patients with a diagnosis of Alström syndrome, confirmed via ALMS1 gene sequencing, are under ongoing review within the UK National MDT Alström service.
MAIN OUTCOME MEASURES
Magnitude and type of hearing loss were analyzed using patients' audiometric data. Deterioration of hearing was calculated using serial pure tone audiograms. Methods of hearing rehabilitation used by patients and potential candidacy for cochlear implantation were analyzed.
RESULTS
Of 34 patients with available audiograms, all had sensorineural hearing loss (SNHL). Dual sensory (visual and hearing) loss was present in 32/34 (94%) patients. Hearing deteriorated with advancing age, at 1.23 dB/yr. Severe- profound SNHL was present in 9/34 (26%) cases. Air conduction hearing aids were used in 27/34 (79%) cases, and cochlear implants in 2/34 (5%).
CONCLUSIONS
Alström syndrome is an ultra-rare genetic disorder with progressive, debilitating multi-system manifestations, including SNHL. The UK National MDT Alström service represents one of the largest reported adult cohorts in the world. SNHL in this group was ubiquitous, showing a rapid decline in hearing with age. Annual audiometric assessment to enable early diagnosis of hearing loss and optimum rehabilitation are paramount to minimize the impact of hearing loss in this condition.
Topics: Adult; Alstrom Syndrome; Deafness; Hearing Loss; Hearing Loss, Sensorineural; Humans; Infant; United Kingdom
PubMed: 35761454
DOI: 10.1097/MAO.0000000000003553 -
American Journal of Ophthalmology Case... Sep 2022To illustrate the importance of systemic evaluation in retinal dystrophies through examples of Alstrom syndrome, Bardet Biedl syndrome, and Refsum disease.
PURPOSE
To illustrate the importance of systemic evaluation in retinal dystrophies through examples of Alstrom syndrome, Bardet Biedl syndrome, and Refsum disease.
OBSERVATIONS
Detailed eye evaluations, including visual acuity, visual field, slit lamp examination, and indirect ophthalmoscopy were performed. Retinal imaging included fundus photography and spectral domain optical coherence tomography (SD-OCT). Functional testing of the retina was done using full field electroretinography (ffERG). In addition, molecular genetic testing was performed using a ciliopathy panel, a retinal dystrophy panel, and whole genome sequencing (WGS).We report three individuals who presented with vision concerns first to ophthalmology, noted to have retinal dystrophy, and then referred to genomic medicine for genetic testing. Additional evaluation led to suspicion of specific groups of systemic disorders and guided appropriate genetic testing. The first individual presented with retinal dystrophy, obesity, and short stature with no reported neurocognitive deficits. Genetic testing included a ciliopathy panel that was negative followed by WGS that identified biallelic variants in : a novel frame-shift pathogenic variant c.6525dupT (p.Gln2176Serfs*17) and a rare nonsense pathogenic variant c.2035C > T (p.Arg679Ter) consistent with Alstrom syndrome. The second individual presented with retinal dystrophy, central obesity, and mild neurocognitive deficits. A ciliopathy genetic testing panel identified a homozygous pathogenic variant in : c.389_390del (p.Asn130Thrfs*4), confirming the diagnosis of Bardet Biedl syndrome. The third individual presented with progressive vision loss due to retinitis pigmentosa, anosmia, hearing loss, and shortened metatarsals and digits. Genetic testing identified two variants in : c.375_375del (p.Glu126Argfs*2) a pathogenic variant and c.536A > G (p.His179Arg), a variant of uncertain significance (VUS), suggestive of Refsum disease. Additional biochemical testing revealed markedly elevated phytanic acid with a low concentration of pristanic acid and normal concentrations of very long-chain fatty acids (C22:0, C24:0, C26:0), a pattern consistent with a diagnosis of Refsum disease.
CONCLUSIONS AND IMPORTANCE
In individuals who present with retinal dystrophy to ophthalmologists, additional systemic manifestations such as sensorineural hearing loss, anosmia, or polydactyly, should be sought and a positive history or examination finding should prompt an immediate referral to a clinical geneticist for additional evaluation and appropriate genetic testing. This facilitates pre-test genetic counseling and allows for more accurate diagnosis, prognosis, and management of affected individuals along with better recurrence risk estimates for family members. Identification of an underlying etiology also enhances the understanding of the pathophysiology of disease and expands the genotypic and phenotypic spectrum. Ultimately, successful recognition of these diseases facilitates development of targeted therapies and surveillance of affected individuals.
PubMed: 35756836
DOI: 10.1016/j.ajoc.2022.101613 -
American Journal of Medical Genetics.... Sep 2022Type 2 diabetes remains rare in the pediatric population and the majority of cases occur during puberty. A combination of genetic and environmental factors leads to the...
Type 2 diabetes remains rare in the pediatric population and the majority of cases occur during puberty. A combination of genetic and environmental factors leads to the development of insulin resistance and β-cell failure. An increased prevalence is recognized in a number of rare genetic disorders such as Alström and Bardet-Biedl syndromes. Recently, a rare neurodevelopmental disorder, Shashi-Pena syndrome due to the dominant negative effect of heterozygous mutations in additional Sex-Combs-Like Genes 2 (ASXL2) has been reported. ASXL2 null mice exhibit glucose intolerance, insulin resistance and lipodystrophy. The regulatory role of ASXL2 in glucose and lipid homeostasis occurs through its interaction with peroxisome proliferator-activated receptor gamma (PPARγ), a gene implicated in the pathogenesis of type 2 diabetes on genome-wide association studies. Thiazolidinediones, used for the treatment of type 2 diabetes, exert their effects as direct agonists of PPARγ. We report the first case of type 2 diabetes in Shashi-Pena syndrome, occurring in an 8-year-old prepubertal boy with no family history. In addition, the proband had dyslipidemia, and fatty infiltration of the liver with elevated transaminases. Mutation of ASXL2 in humans, through its interaction with PPARγ appears to cause a phenotype of insulin resistance, type 2 diabetes, and dyslipidemia. Further reported cases will assist in confirming this association.
Topics: Animals; Child; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Humans; Insulin Resistance; Male; Mice; Mutation; PPAR gamma; Repressor Proteins
PubMed: 35716351
DOI: 10.1002/ajmg.a.62876 -
Intractable & Rare Diseases Research May 2022Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the () gene, located on chromosome 2p13. It is a progressive...
Alström syndrome (AS) is a rare autosomal recessive monogenic disorder caused by mutations of the () gene, located on chromosome 2p13. It is a progressive multisystemic disease characterized mostly by obesity, sensorineural hearing loss, visual impairments, cardiomyopathy, insulin resistance and/or type 2 diabetes mellitus (T2DM), metabolic dysfunctions, non-alcoholic fatty liver disease, and chronic progressive kidney disease. Generally, the first clinical symptoms of the disease appear in the first years of life with a major variation of onset age. In this study, we aimed to examine the molecular diagnosis of a 6-year-old patient with suspected AS clinical symptoms. After applying clinical exome sequencing (CES) in the patient we found a homozygous deletion in exon 8 at the gene (c.2311_2312del). We identified a homozygous frameshift mutation. The reported variant was pathogenic according to the criteria of the American College of Medical Genetics and Genomics (ACMG). Thus, the patient was diagnosed with AS as a result of the combined clinical phenotype and genetic tests results. We hope the variant we found can expand the spectrum of variants in AS.
PubMed: 35702577
DOI: 10.5582/irdr.2022.01024 -
Translational Pediatrics Apr 2022Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset...
BACKGROUND
Alstrom syndrome (ALMS) is a rare genetic disorder. ALMS is characterized by progressive bilateral sensorineural hearing impairment, cone-rod dystrophy, infantile-onset cardiomyopathy, hypertriglyceridemia, accelerated non-alcoholic fatty liver disease, renal dysfunction and insulin-resistant diabetes mellitus (DM). DM typically develop in childhood or adolescence. Dilated cardiomyopathy may arise in infancy. Clinical symptoms appear with great variability and severity. Several cases have been reported worldwide; however, diagnosis remains challenging.
CASE DESCRIPTION
We report an 8-year-and-11-month-old female diagnosed with ALMS who had a long history of obesity and amblyopia from infancy. We found high levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in this patient. She showed no hearing disfunction. Recently, she presented with sudden-onset insulin-resistant DM. Genetic analysis revealed the heterozygous mutations c.8366delT, p.L2789* and c.6829C>T, p.R2277*. c.8366delT, which results in premature protein termination, has not been reported previously in . Although the patient's two sisters died of acute heart failure following infection at 4 and 14 months respectively, she showed no signs of cardiomyopathy until now.
CONCLUSIONS
This case provides an unusual cause of genetic syndrome associated with diabetes. A detailed medical history, physical examination and appropriate gene analysis are critical for diagnosis. Our case identifies a novel mutation and reaffirms the great clinical variation of this disease even within families.
PubMed: 35558979
DOI: 10.21037/tp-21-623 -
Translational Pediatrics Apr 2022Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem...
BACKGROUND
Alstrom syndrome (ALMS) is an ultra-rare multisystem genetic disorder caused by autosomal recessive inheritance of the ALMS1 gene. It manifests as multisystem dysfunction, displaying unique clinical signs and symptoms and various severity, which may lead to delayed prognosis or misdiagnosis in medical practice. Although almost 300 pathogenic variants have been reported, there are some variant sites that have not been recognized yet.
CASE DESCRIPTION
We report a case of a 14-year-old boy with manifestations, including binocular vision loss, acanthosis nigricans, type 2 diabetes, insulin resistance, elevated transaminase, hepatic fibrosis, and proteinuria. Compound heterozygous variants in the gene have been discovered by whole exon sequencing. One of his variant sites was C. 8158C>T, which was from his father. And the other variant site was C. 3575C>A, which was from his mother. To the great of our knowledge, this site has not been reported before. Both of the variants make the synthesis of the peptide chain terminated in advance and an incomplete polypeptide chain is formed.
CONCLUSIONS
The clinical presentations of ALMS are complicated and varied. Although early diagnosis can be made according to typical clinical symptoms, whole exon sequencing is necessary for the diagnosis of ALMS, as indicated by our study.
PubMed: 35558973
DOI: 10.21037/tp-21-535