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1.  A Role for Alström Syndrome Protein, Alms1, in Kidney Ciliogenesis and Cellular Quiescence  
PLoS Genetics  2007;3(1):e8.
Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia.
Author Summary
Alström syndrome is a rare genetic disorder caused by mutations in the ALMS1 gene. The disease is characterized by blindness, deafness, and metabolic disorders. These symptoms are reminiscent of diseases affecting the primary cilium, a cellular appendage with a role in sensing changes to the extracellular environment. In addition, kidney failure is a frequent cause of death in Alström syndrome patients, and recent studies have suggested a causal relationship between defects in primary cilia and cystic kidney diseases. In this paper, we show that ALMS1 protein is required to form cilia in kidney cells. Mutant alleles of the gene that are similar to those seen in the human disease are able to support cilia formation in cell culture and in animals. However, a defect in the function of the disease alleles is uncovered in older mice: cilia are lost from the kidney cells, and this is associated with an increase in cellular proliferation and cell death. The data are consistent with a requirement for ALMS1 in ciliogenesis and suggest inclusion of Alström syndrome among the growing class of cilia-related pathologies.
PMCID: PMC1761047  PMID: 17206865
2.  The Alström Syndrome Protein, ALMS1, Interacts with α-Actinin and Components of the Endosome Recycling Pathway 
PLoS ONE  2012;7(5):e37925.
Alström syndrome (ALMS) is a progressive multi-systemic disorder characterized by cone-rod dystrophy, sensorineural hearing loss, childhood obesity, insulin resistance and cardiac, renal, and hepatic dysfunction. The gene responsible for Alström syndrome, ALMS1, is ubiquitously expressed and has multiple splice variants. The protein encoded by this gene has been implicated in ciliary function, cell cycle control, and intracellular transport. To gain better insight into the pathways through which ALMS1 functions, we carried out a yeast two hybrid (Y2H) screen in several mouse tissue libraries to identify ALMS1 interacting partners. The majority of proteins found to interact with the murine carboxy-terminal end (19/32) of ALMS1 were α-actinin isoforms. Interestingly, several of the identified ALMS1 interacting partners (α-actinin 1, α-actinin 4, myosin Vb, rad50 interacting 1 and huntingtin associated protein1A) have been previously associated with endosome recycling and/or centrosome function. We examined dermal fibroblasts from human subjects bearing a disruption in ALMS1 for defects in the endocytic pathway. Fibroblasts from these patients had a lower uptake of transferrin and reduced clearance of transferrin compared to controls. Antibodies directed against ALMS1 N- and C-terminal epitopes label centrosomes and endosomal structures at the cleavage furrow of dividing MDCK cells, respectively, suggesting isoform-specific cellular functions. Our results suggest a role for ALMS1 variants in the recycling endosome pathway and give us new insights into the pathogenesis of a subset of clinical phenotypes associated with ALMS.
PMCID: PMC3365098  PMID: 22693585
3.  Centriolar Association of ALMS1 and Likely Centrosomal Functions of the ALMS Motif–containing Proteins C10orf90 and KIAA1731 
Molecular Biology of the Cell  2010;21(21):3617-3629.
This study reveals the subcentrosomal distribution of ALMS1, a human protein implicated in primary cilium formation and maintenance, and provides new insight into its centrosome-related functions. The first functional data on two human proteins sharing C-terminal sequence similarity with ALMS1 are also presented.
Mutations in the human gene ALMS1 cause Alström syndrome, a rare progressive condition characterized by neurosensory degeneration and metabolic defects. ALMS1 protein localizes to the centrosome and has been implicated in the assembly and/or maintenance of primary cilia; however its precise function, distribution within the centrosome, and mechanism of centrosomal recruitment are unknown. The C-terminus of ALMS1 contains a region with similarity to the uncharacterized human protein C10orf90, termed the ALMS motif. Here, we show that a third human protein, the candidate centrosomal protein KIAA1731, contains an ALMS motif and that exogenously expressed KIAA1731 and C10orf90 localize to the centrosome. However, based on deletion analysis of ALMS1, the ALMS motif appears unlikely to be critical for centrosomal targeting. RNAi analyses suggest that C10orf90 and KIAA1731 have roles in primary cilium assembly and centriole formation/stability, respectively. We also show that ALMS1 localizes specifically to the proximal ends of centrioles and basal bodies, where it colocalizes with the centrosome cohesion protein C-Nap1. RNAi analysis reveals markedly diminished centrosomal levels of C-Nap1 and compromised cohesion of parental centrioles in ALMS1-depleted cells. In summary, these data suggest centrosomal functions for C10orf90 and KIAA1731 and new centriole-related functions for ALMS1.
PMCID: PMC2965680  PMID: 20844083
4.  Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity 
Human Molecular Genetics  2010;20(3):466-481.
Alström Syndrome is a life-threatening disease characterized primarily by numerous metabolic abnormalities, retinal degeneration, cardiomyopathy, kidney and liver disease, and sensorineural hearing loss. The cellular localization of the affected protein, ALMS1, has suggested roles in ciliary function and/or ciliogenesis. We have investigated the role of ALMS1 in the cochlea and the pathogenesis of hearing loss in Alström Syndrome. In neonatal rat organ of Corti, ALMS1 was localized to the basal bodies of hair cells and supporting cells. ALMS1 was also evident at the basal bodies of differentiating fibrocytes and marginal cells in the lateral wall. Centriolar ALMS1 expression was retained into maturity. In Alms1-disrupted mice, which recapitulate the neurosensory deficits of human Alström Syndrome, cochleae displayed several cyto-architectural defects including abnormalities in the shape and orientation of hair cell stereociliary bundles. Developing hair cells were ciliated, suggesting that ciliogenesis was largely normal. In adult mice, in addition to bundle abnormalities, there was an accelerated loss of outer hair cells and the progressive appearance of large lesions in stria vascularis. Although the mice progressively lost distortion product otoacoustic emissions, suggesting defects in outer hair cell amplification, their endocochlear potentials were normal, indicating the strial atrophy did not affect its function. These results identify previously unrecognized cochlear histopathologies associated with this ciliopathy that (i) implicate ALMS1 in planar cell polarity signaling and (ii) suggest that the loss of outer hair cells causes the majority of the hearing loss in Alström Syndrome.
PMCID: PMC3016908  PMID: 21071598
5.  Alms1-disrupted mice recapitulate human Alström syndrome 
Human molecular genetics  2005;14(16):2323-2333.
Mutations in the human ALMS1 gene cause Alström syndrome (AS), a progressive disease characterized by neurosensory deficits and by metabolic defects including childhood obesity, hyperinsulinemia and Type 2 diabetes. Other features that are more variable in expressivity include dilated cardiomyopathy, hypertrigly-ceridemia, hypercholesterolemia, scoliosis, developmental delay and pulmonary and urological dysfunctions. ALMS1 encodes a ubiquitously expressed protein of unknown function. To obtain an animal model in which the etiology of the observed pathologies could be further studied, we generated a mouse model using an Alms1 gene-trapped ES cell line. Alms1−/− mice develop features similar to patients with AS, including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction and late-onset hearing loss. Insulin resistance and increased body weight are apparent between 8 and 12 weeks of age, with hyperglycemia manifesting at ~16 weeks of age. In addition, Alms1−/− mice have normal hearing until 8 months of age, after which they display abnormal auditory brainstem responses. Diminished cone ERG b-wave response is observed early, followed by the degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analysis showed mislocalization of rhodopsin to the outer nuclear layer. These findings suggest that ALMS1 has a role in intracellular trafficking.
PMCID: PMC2862911  PMID: 16000322
6.  Coronary artery disease in Alström syndrome 
Alström syndrome (ALMS) is a rare autosomal recessive condition, caused by mutations in the ALMS1 gene located on the short arm of chromosome 2. This gene codes for a protein linked with the centrosome, whose precise function is unknown. This condition was first described by Alström in 1959. ALMS is a multisystem condition that is characterised by childhood onset of blindness secondary to rod-cone retinal degeneration and dilated cardiomyopathy with heart failure, which often presents in infanthood and may recur later in life. Metabolic abnormalities including hypertriglyceridemia, liver steatosis, insulin resistance and type 2 diabetes mellitus are common, often occurring in association with obesity. Other abnormalities include endocrinological disturbances, such as thyroid disorder, growth hormone deficiency, hypogonadism and, in women, hyperandrogenism. This syndrome is also associated with sensorineural hearing loss, renal failure secondary to glomerulo-fibrosis, and fibrotic lung disease. Multiorgan fibrotic infiltration is the common feature in all cases. Considering the history of diabetes, hypertension, dyslipidemia, obesity and renal dysfunction in ALMS, it would be expected that this group of patients could develop coronary artery disease (CAD). But such cases have not been reported so far. We report a case of premature onset of CAD in one of the longest surviving patient with ALMS.
PMCID: PMC3234522  PMID: 21897446
Alström syndrome; complications; coronary artery disease
7.  Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader–Willi and Alström syndromes 
Advances in genomics and genetics  2015;2015(5):53-75.
Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader–Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.
PMCID: PMC4334166  PMID: 25705109
hyperphagia; microarray analysis; gene; obesity; exon expression; miRNA expression
8.  Transcriptional regulation of the Alström syndrome gene ALMS1 by members of the RFX family and Sp1 
Gene  2010;460(1-2):20-29.
Mutations in the human gene ALMS1 cause Alström syndrome, a disorder characterised by neurosensory degeneration, metabolic defects and cardiomyopathy. ALMS1 encodes a centrosomal protein implicated in the assembly and maintenance of primary cilia. Expression of ALMS1 varies between tissues and recent data suggest that its transcription is modulated during adipogenesis and growth arrest. However the ALMS1 promoter has not been defined. This study focused on identifying and characterising the ALMS1 proximal promoter, initially by using 5' RACE to map transcription start sites. Luciferase reporter assay and EMSA data strongly suggest that ALMS1 transcription is regulated by the ubiquitous factor Sp1. In addition, reporter assay, EMSA, chromatin immunoprecipitation and RNA interference data indicate that ALMS1 transcription is regulated by regulatory factor X (RFX) proteins. These transcription factors are cell-type restricted in their expression profile and known to regulate genes of the ciliogenic pathway. We show binding of RFX proteins to an evolutionarily conserved X-box in the ALMS1 proximal promoter and present evidence that these proteins are responsible for ALMS1 transcription during growth arrest induced by low serum conditions. In summary, this work provides the first data on transcription factors regulating general and context-specific transcription of the disease-associated gene ALMS1.
PMCID: PMC2913254  PMID: 20381594
CAGE, cap-analysis of gene expression; cDNA, DNA complementary to RNA; ChIP, chromatin immunoprecipitation; EMSA, electrophoretic mobility shift assay; FCS, fetal calf serum; LMC, low-mobility complex; NE, nuclear extract; PCR, polymerase chain reaction; RACE, rapid amplification of cDNA ends; RFX, regulatory factor X; RNAi, RNA interference; RT-PCR, reverse transcription-PCR; s.d., standard deviation; SDS-PAGE, sodium dodecyl sulfate polyacrylamide gel electrophoresis; s.e.m., standard error of the mean; siRNA, small interfering RNA; TBP, TATA-binding protein; TSS, transcription start site; transcription; promoter; X-box; GC-box; cilia
9.  The progression from obesity to type 2 diabetes in Alström syndrome 
Pediatric Diabetes  2011;13(1):59-67.
Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease associated with obesity, hyperinsulinemia and alterations of glucose metabolism that often lead to the development of type 2 diabetes in a young age.
Relationship between weight and metabolism has been studied in a group of ALMS patients and matched controls.
Research design and methods
Fifteen ALMS patients (8 M, 7 F, aged 3-51 yrs) were compared in a cross-sectional study with an age- and weight-matched control population. Anthropometric parameters, fat mass, glucose and insulin secretion in basal and dynamic (OGTT) conditions were measured. Further anthropometric and body composition data were obtained from an International group of 27 ALMS patients (13 M, 14 F, age range: 4-29 yrs).
In ALMS we observed an inverse correlation between age and SDS for height, weight and BMI. The OGTT glycemic curves of ALMS subjects were similar to those of age-matched controls, while insulin response was clearly greater. In ALMS individuals the insulin response showed a reduction with age. We documented pathologic values of the derived indices HOMA-IR, ISI, HOMA%β cell and Insulinogenic Index in ALMS, but unlike the insulin-resistance indices, the beta-cell function indices showed a significant reduction with age.
In ALMS the progression from the early onset obesity towards the impaired fasting glucose or IGT and overt diabetes is mostly due to a progressive failure of β-cell insulin secretion without any further worsening of insulin resistance with age, even in the presence of weight reduction.
PMCID: PMC3345208  PMID: 21722283
Alström syndrome; ALMS1; obesity; diabetes; insulin resistance
10.  Novel Alu Retrotransposon Insertion Leading to Alström Syndrome 
Human Genetics  2011;131(3):407-413.
Alström Syndrome is a clinically complex disorder characterized by childhood retinal degeneration leading to blindness, sensorineural hearing loss, obesity, type 2 diabetes mellitus, cardiomyopathy, systemic fibrosis, and pulmonary, hepatic, and renal failure. Alström Syndrome is caused by recessively inherited mutations in the ALMS1 gene, which codes for a putative ciliary protein. Alström Syndrome is characterized by extensive allelic heterogeneity, however founder effects have been observed in some populations. To date, more than 100 causative ALMS1 mutations have been identified, mostly frameshift and nonsense alterations resulting in termination signals in ALMS1. Here we report a complex Turkish kindred in which sequence analysis uncovered an insertion of a novel 333 basepair Alu Ya5 SINE retrotransposon in the ALMS1 coding sequence, a previously unrecognized mechanism underlying mutations causing Alström Syndrome. It is extraordinarily rare to encounter the insertion of an Alu retrotransposon in the coding sequence of a gene. The high frequency of the mutant ALMS1 allele in this isolated population suggests that this recent retrotransposition event spread quickly, and may be used as a model to study the population dynamics of deleterious alleles in isolated communities.
PMCID: PMC3264847  PMID: 21877133
Alström Syndrome; ALMS1; Alu Ya5; Insertion Mutation; Short Interspersed Nuclear Elements (SINE)
11.  Differences in the clinical spectrum of two adolescent male patients with Alström syndrome 
Clinical dysmorphology  2013;22(1):7-12.
Alström syndrome is a rare disorder typified by early childhood obesity, neurosensory deficits, cardiomyopathy, progressive renal and hepatic dysfunction, and endocrinological features such as severe insulin resistance, type 2 diabetes, hyperlipidemia, and hypogonadism. Widespread fibrosis leads to multiple organ failure. Mutations in ALMS1 cause Alström’s syndrome. Two age-matched, unrelated adolescent males of Serbian descent with Alström syndrome underwent an extensive workup of blood chemistries, and ophthalmological, audiological, and genetic evaluations. Although both showed typical features of Alström syndrome in childhood, several differences were observed that have not been reported previously. Patient 1 was first studied at the age of 13 years for multisystemic disease and re-evaluated at the age of 15.5 years. Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic–clonic seizures with severe cognitive impairment, features not documented previously in this syndrome. Sequencing analysis indicated two novel ALMS1 mutations in exon 8: p.E1055GfsX4 and p.T1386NfsX15. Metabolic and physiological similarities were observed in both patients, including severe insulin resistance, and truncal obesity with fat loss suggestive of partial lipodystrophy, supporting evidence for a role for ALMS1 in adipose tissue function. The unusual phenotypes of clonic–tonic seizures and severe cognitive abnormalities and lipodystrophy-like adiposity pattern have not been documented previously in Alström syndrome and may be an under-reported abnormality.
PMCID: PMC3619948  PMID: 23188138
ALMS1; Alström syndrome; hypogonadotropic hypogonadism; partial lipodystrophy; tonic–clonic epilepsy
12.  Alström Syndrome: Genetics and Clinical Overview 
Current Genomics  2011;12(3):225-235.
Alström syndrome is a rare autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy, and progressive pulmonary, hepatic, and renal dysfunction. Symptoms first appear in infancy and progressive development of multi-organ pathology leads to a reduced life expectancy. Variability in age of onset and severity of clinical symptoms, even within families, is likely due to genetic background.
Alström syndrome is caused by mutations in ALMS1, a large gene comprised of 23 exons and coding for a protein of 4,169 amino acids. In general, ALMS1 gene defects include insertions, deletions, and nonsense mutations leading to protein truncations and found primarily in exons 8, 10 and 16. Multiple alternate splice forms exist. ALMS1 protein is found in centrosomes, basal bodies, and cytosol of all tissues affected by the disease. The identification of ALMS1 as a ciliary protein explains the range of observed phenotypes and their similarity to those of other ciliopathies such as Bardet-Biedl syndrome.
Studies involving murine and cellular models of Alström syndrome have provided insight into the pathogenic mechanisms underlying obesity and type 2 diabetes, and other clinical problems. Ultimately, research into the pathogenesis of Alström syndrome should lead to better management and treatments for individuals, and have potentially important ramifications for other rare ciliopathies, as well as more common causes of obesity and diabetes, and other conditions common in the general population.
PMCID: PMC3137007  PMID: 22043170
ALMS1; Alström syndrome; ciliopathy; truncal obesity.
13.  GLUT4 Defects in Adipose Tissue Are Early Signs of Metabolic Alterations in Alms1GT/GT, a Mouse Model for Obesity and Insulin Resistance 
PLoS ONE  2014;9(10):e109540.
Dysregulation of signaling pathways in adipose tissue leading to insulin resistance can contribute to the development of obesity-related metabolic disorders. Alström Syndrome, a recessive ciliopathy, caused by mutations in ALMS1, is characterized by progressive metabolic alterations such as childhood obesity, hyperinsulinemia, and type 2 diabetes. Here we investigated the role of Alms1 disruption in AT expansion and insulin responsiveness in a murine model for Alström Syndrome. A gene trap insertion in Alms1 on the insulin sensitive C57BL6/Ei genetic background leads to early hyperinsulinemia and a progressive increase in body weight. At 6 weeks of age, before the onset of the metabolic disease, the mutant mice had enlarged fat depots with hypertrophic adipocytes, but without signs of inflammation. Expression of lipogenic enzymes was increased. Pre-adipocytes isolated from mutant animals demonstrated normal adipogenic differentiation but gave rise to mature adipocytes with reduced insulin-stimulated glucose uptake. Assessment of whole body glucose homeostasis revealed glucose intolerance. Insulin stimulation resulted in proper AKT phosphorylation in adipose tissue. However, the total amount of glucose transporter 4 (SLC4A2) and its translocation to the plasma membrane were reduced in mutant adipose depots compared to wildtype littermates. Alterations in insulin stimulated trafficking of glucose transporter 4 are an early sign of metabolic dysfunction in Alström mutant mice, providing a possible explanation for the reduced glucose uptake and the compensatory hyperinsulinemia. The metabolic signaling deficits either reside downstream or are independent of AKT activation and suggest a role for ALMS1 in GLUT4 trafficking. Alström mutant mice represent an interesting model for the development of metabolic disease in which adipose tissue with a reduced glucose uptake can expand by de novo lipogenesis to an obese state.
PMCID: PMC4192353  PMID: 25299671
14.  Polymyxin B Resistance and Biofilm Formation in Vibrio cholerae Are Controlled by the Response Regulator CarR 
Infection and Immunity  2015;83(3):1199-1209.
Two-component systems play important roles in the physiology of many bacterial pathogens. Vibrio cholerae's CarRS two-component regulatory system negatively regulates expression of vps (Vibrio polysaccharide) genes and biofilm formation. In this study, we report that CarR confers polymyxin B resistance by positively regulating expression of the almEFG genes, whose products are required for glycine and diglycine modification of lipid A. We determined that CarR directly binds to the regulatory region of the almEFG operon. Similarly to a carR mutant, strains lacking almE, almF, and almG exhibited enhanced polymyxin B sensitivity. We also observed that strains lacking almE or the almEFG operon have enhanced biofilm formation. Our results reveal that CarR regulates biofilm formation and antimicrobial peptide resistance in V. cholerae.
PMCID: PMC4333464  PMID: 25583523
15.  Novel ALMS1 mutations in Chinese patients with Alström syndrome 
Molecular Vision  2013;19:1885-1891.
Alström syndrome (AS) is a rare monogenic autosomal recessively inherited disorder characterized by cone rod dystrophy and multiple organ dysfunction. Mutations in the Alström syndrome 1 (ALMS1) gene have been found to be causative for AS. The purpose of this study was to identify ALMS1 mutations and to assess the clinical features of Chinese patients with AS.
Detailed ocular and laboratory examinations were performed. Peripheral blood samples were collected from patients and their parents. Genomic DNA was extracted with a Qiagen kit. Exons and exon/intron junctions of ALMS1 were amplified with polymerase chain reaction (PCR) and screened for mutations with Sanger sequencing. The results were compared with the ALMS1 transcript to exclude polymorphisms and confirm pathogenic mutations.
Seven patients from five unrelated non-consanguineous families were diagnosed with AS. All patients had cone rod dystrophy with impaired visual acuity, photophobia, and nystagmus. Other clinical features, including sensorineural hearing loss, truncal obesity, insulin resistance, type 2 diabetes mellitus, renal and hepatic dysfunction, hyperlipidemia, hypothyroidism, mental retardation, acanthosis nigricans, and scoliosis, were present. Sequencing revealed two novel mutations, p.N3150Kfs2X and p.V3154Xfs, in patient 1; one novel mutation, p.N3672Ifs11X, and one previously reported nonsense mutation, p.R3703X, in patient 2; novel mutations p.S2479X and p.R3611Efs7X in patient 3; one novel homozygous mutation, p.S695X, in patients 4 and 5; and two novel mutations, p.H688HfsX and p.Q3147Qfs2X, in patients 6 and 7. These mutations were not present in 100 unrelated healthy Chinese control subjects. The patients’ parents were heterozygous carriers of the mutant allele.
Seven Chinese patients with AS showed typical ophthalmic features and multiple organ dysfunction. Novel loss of function mutations in the ALMS1 gene are the underlying genetic defects.
PMCID: PMC3774572  PMID: 24049434
16.  Targeting ErbB2 and ErbB3 with a Bispecific-Single Chain Fv Enhances Targeting Selectivity and Induces a Therapeutic Effect in vitro 
British journal of cancer  2008;99(9):1415-1425.
Inappropriate signaling through the EGFR and ErbB2/HER2 members of the epidermal growth factor family of receptor tyrosine kinases is well recognized as being causally linked to a variety of cancers (Hynes and Lane 2005). Consequently, monoclonal antibodies (MAbs) specific for these receptors have become increasingly important components of effective treatment strategies for cancer. Increasing evidence suggests that ErbB3 plays a criticial role in cancer progression and resistance to therapy. We hypothesized that co-targeting the preferred ErbB2/ErbB3 heterodimer with a bispecific single chain-Fv (bs-scFv) antibody would promote increased targeting selectivity over antibodies specific for a single tumor associated antigen (TAA). In addition, we hypothesized that targeting this important heterodimer could induce a therapeutic effect. Here we describe the construction and evaluation of ALM, an anti-ErbB3/ErbB2 bs-scFv. ALM exhibits selective targeting of tumor cells in vitro and in vivo that co-express the two target antigens over tumor cells that express only one target antigen or normal cells that express low levels of both antigens. ALM also exhibits significantly greater in vivo targeting of ErbB2“+”/ErbB3“+” tumors than derivative molecules that contain only one functional arm targeting ErbB2 or ErbB3. Binding of ALM to ErbB2“+”/ErbB3“+” mediates inhibition of tumor cell growth in vitro by effectively targeting the therapeutic anti-ErbB3 A5 scFv. This suggests both that ALM could provide the basis for an effective therapeutic agent and that engineered antibodies selected to co-target critical functional pairs of TAAs can enhance the targeting specificity and efficacy of antibody-based cancer therapeutics.
PMCID: PMC2576487  PMID: 18841159
engineered antibody; bispecific; ErbB
17.  Alström Syndrome: Cardiac Magnetic Resonance findings 
International journal of cardiology  2012;167(4):1257-1263.
Alström Syndrome (ALMS) is an extremely rare multiorgan disease caused by mutations in ALMS1. Dilated Cardiomyopathy (DCM) is a common finding but only one series has been investigated by Cardiac Magnetic Resonance (CMR).
Eight genetically proven ALMS patients (ages 11–41) underwent CMR performed by standard cine steady state, T1, T2 and Late Gadolinium Enhancement (LGE) sequences. Ejection fraction (EF), Diastolic Volume (EDV) and Systolic Volume normalized for body surface area (ESV), and Mass indices were determined, as well as EDV/Mass ratio, an index expressing the adequacy of cardiac mass to heart volume. Regional fibrosis was assessed by LGE; diffuse fibrosis was measured by a TI scout sequence acquired at 5, 10 and 15 min after gadolinium by comparing inversion time values (TI) at null time in ALMS and control group.
In one patient severe DCM was present with diffuse LGE. There were seven cases without clinical DCM. In these patients, EF was at lower normal limits or slightly reduced and ESV index increased; six patients had decreased Mass index and EDV/Mass ratio. Mild regional non ischemic fibrosis was detected by LGE in three cases; diffuse fibrosis was observed in all cases, as demonstrated by shorter TI values in ALMS in comparison with controls (5 min:152±12 vs 186±16, p 0,0002; 10 min: 175±8 vs 204±18, p 0,0012; 15 min: 193± 9 vs 224±16, p 0,0002).
Cardiac involvement in ALMS is characterized by progressive DCM, associated with systolic dysfunction, myocardial fibrosis and reduced myocardial mass.
PMCID: PMC3422598  PMID: 22498418
Alström Syndrome; ALMS1; Dilated cardiomyopathy; Cardiac Magnetic Resonance; fibrosis
18.  Alström syndrome: current perspectives 
Alström syndrome (ALMS) is a rare genetic disorder that has been included in the ciliopathies group, in the last few years. Ciliopathies are a growing group of diseases associated with defects in ciliary structure and function. The development of more powerful genetic approaches has been replaced the strategies to follow for getting a successful molecular diagnosis for these patients, especially for those without the typical ALMS phenotype. In an effort to deepen the understanding of the pathogenesis of ALMS disease, much work has been done, in order to establish the biological implication of ALMS1 protein, which is still being elucidated. In addition to its role in ciliary function and structure maintenance, this protein has been implicated in intracellular trafficking, regulation of cilia signaling pathways, and cellular differentiation, among others. All these progresses will lead to identifying therapeutic targets, thus opening the way to future personalized therapies for human ciliopathies.
PMCID: PMC4516341
Alström syndrome; ciliopathies; ALMS1 gene; ALMS1 protein; molecular diagnosis
19.  Alström Syndrome is associated with short stature and reduced GH reserve 
Clinical endocrinology  2013;79(4):529-536.
Alström Syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called ‘ciliopathies’ and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thusfar no study has specifically investigated this aspect in a large population.
Material and Methods
Twenty-three ALMS patients (age 1-52 years, 11 M, 12 F) were evaluated for anthropometric parameters (growth charts and Standard Deviation Score (SDS) of height, weight, BMI), GH secretion by growth-hormone-releasing-hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized.
The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0,67 SDS to +1.28 SDS. A progressive decrease of stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (> 16-20 years: mean SDS -2.22±1.16). The subset of 12 ALMS patients tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154.7±10.6 cm vs 162.9±4.8 cm, p= 0.009), and a mild increase of BMI (Kg/m2) (27.8±4.8 vs 24.1±2.5, p=0.007). Peak GH after GHRH-arg was significantly lower in ALMS patients in comparison to controls (11.9±6.9 ug/L vs 86.1±33.2 ug/L, p <0,0001). Severe GHD was evident biochemically in 50% of ALMS patients. The 10 adult ALMS patients with GHD showed a reduced height in comparison to those without GHD (149.7±6.2 cm vs 161.9±9.2 cm, p= 0.04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases.
Our study shows that 50% of non-obese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.
PMCID: PMC3718851  PMID: 23445176
Alström Syndrome; ALMS1; GH; arginine; recombinant GH (rGH); fibrosis
20.  Mutations in Alström Protein Impair Terminal Differentiation of Cardiomyocytes 
Nature communications  2014;5:3416.
Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognise homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at two weeks postnatal compared to wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.
PMCID: PMC3992616  PMID: 24595103
21.  Bivariate Genome-Wide Association Analyses of Femoral Neck Bone Geometry and Appendicular Lean Mass 
PLoS ONE  2011;6(11):e27325.
Femoral neck geometric parameters (FNGPs), such as periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are highly genetically correlated with body lean mass. However, the specific SNPs/genes shared by these phenotypes are largely unknown.
To identify the specific SNPs/genes shared between FNGPs and appendicular lean mass (ALM), we performed an initial bivariate genome-wide association study (GWAS) by scanning ∼690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) and a follow-up replicate study in 2,286 unrelated US Caucasians.
We identified 13 interesting SNPs that may be important for both FNGPs and ALM. Two SNPs, rs681900 located in the HK2 (hexokinase 2) gene and rs11859916 in the UMOD (uromodulin) gene, were bivariately associated with FNGPs and ALM (p = 7.58×10−6 for ALM-BR and p = 2.93×10−6 for ALM-W, respectively). The associations were then replicated in Caucasians, with corresponding p values of 0.024 for rs681900 and 0.047 for rs11859916. Meta-analyses yielded combined p values of 3.05×10−6 and 2.31×10−6 for rs681900 and rs11859916, respectively. Our findings are consistent with previous biological studies that implicated HK2 and UMOD in both FNGPs and ALM. Our study also identified a group of 11 contiguous SNPs, which spanned a region of ∼130 kb, were bivariately associated with FNGPs and ALM, with p values ranging from 3.06×10−7 to 4.60×10−6 for ALM-BR. The region contained two neighboring miRNA coding genes, MIR873 (MicroRNA873) and MIR876 (MicroRNA876).
Our study implicated HK2, UMOD, MIR873 and MIR876, as pleiotropic genes underlying variation of both FNGPs and ALM, thus suggesting their important functional roles in co-regulating both FNGPs and ALM.
PMCID: PMC3210160  PMID: 22087292
22.  Population Genomic Analysis of ALMS1 in Humans Reveals a Surprisingly Complex Evolutionary History 
Molecular Biology and Evolution  2009;26(6):1357-1367.
Mutations in the human gene ALMS1 result in Alström Syndrome, which presents with early childhood obesity and insulin resistance leading to Type 2 diabetes. Previous genomewide scans for selection in the HapMap data based on linkage disequilibrium and population structure suggest that ALMS1 was subject to recent positive selection. Through a detailed population genomic analysis of existing genomewide data sets and new resequencing data obtained in geographically diverse populations, we find that the signature of selection at ALMS1 is considerably more complex than what would be expected for an idealized model of a selective sweep acting on a newly arisen advantageous mutation. Specifically, we observed three highly divergent and globally dispersed haplogroups, two of which carry a set of seven derived nonsynonymous single nucleotide polymorphisms that are nearly fixed in Asian populations. Our data suggest that the interaction of human demographic history and positive selection on standing variation in Eurasian populations approximately 15 thousand years ago parsimoniously explains the spectrum of extant ALMS1 variation. These results provide new insights into the evolutionary history of ALMS1 in humans and suggest that selective events identified in genomewide scans may be more complex than currently appreciated.
PMCID: PMC2734137  PMID: 19279085
ALMS1; positive selection; standing variation
23.  Polyomavirus late leader region serves an essential spacer function necessary for viability and late gene expression. 
Journal of Virology  1986;58(2):417-425.
All three polyomavirus late mRNAs contain multiple tandem copies of the same nontranslated 57-nucleotide sequence, the late leader, at their 5' ends. We show here that a polyoma variant (ALM) lacking 48 central bases of the 57-base leader unit is nonviable by plaque assay and by a new method for testing virus viability, an immunofluorescence burst assay. ALM is, however, unaffected in early gene expression as measured both by indirect immunofluorescence of large T antigen and by transformation levels of rat F-111 cells. DNA replication in mouse cells is also as wild type, and the defect in ALM is complemented by an early-defective helper virus DNA. ALM does not make detectable levels of late viral proteins and is minimally 200-fold depressed in the accumulation of cytoplasmic polyadenylated late RNA. When the deleted leader sequence of ALM is replaced by a variety of procaryotic sequences, viability almost always returns. Some of the substituted leader variants produce plaques with the same apparent kinetics as wild-type viral DNA. The indication is that the sequence of the polyoma late leader is not important for late gene expression but that it has an essential spacer function on the RNA or DNA level. This spacer function is apparently necessary for late viral RNA transcription, processing, or stability.
PMCID: PMC252927  PMID: 3009856
24.  Extreme clinical variability of dilated cardiomyopathy in two siblings with Alström syndrome 
Pediatric cardiology  2012;34(2):455-458.
Alström syndrome (ALMS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report on two brothers, 2 and 3 years of age, diagnosed with Alström syndrome who initially presented in infancy with severe dilated cardiomyopathy during febrile respiratory infection. The disease course in the two siblings was marked by significant intra-familial variability. While cardiomyopathy in the older sibling has mainly resolved allowing for the discontinuation of medical therapy, heart function in the younger sibling continues to deteriorate despite maximal drug support with furosemide, carvedilol, captopril and aldospirone. Genetic analysis revealed homozygous mutations, c.8008C>T (R2670X), in ALMS1 resulting in premature protein truncation. This report further emphasizes the exceptional intra-familial variability of ALMS, mainly in the natural course of cardiac disease.
PMCID: PMC3779600  PMID: 22447358
Alström syndrome; dilated cardiomyopathy; autosomal recessive; ALMS1 gene
25.  Antimicrobial Peptide Resistance of Vibrio cholerae Results from an LPS Modification Pathway Related to Nonribosomal Peptide Synthetases 
ACS Chemical Biology  2014;9(10):2382-2392.
The current pandemic El Tor biotype of O1 Vibrio cholerae is resistant to polymyxins, whereas the previous pandemic strain of the classical biotype is polymyxin sensitive. The almEFG operon found in El Tor V. cholerae confers >100-fold resistance to polymyxins through the glycylation of lipopolysaccharide. Here, we present the mechanistic determination of initial steps in the AlmEFG pathway. We verify that AlmF is an aminoacyl carrier protein and identify AlmE as the enzyme required to activate AlmF as a functional carrier protein. A combination of structural information and activity assays was used to identify a pair of active site residues that are important for mediating AlmE glycine specificity. Overall, the structure of AlmE in complex with its glycyl-adenylate intermediate reveals that AlmE is related to Gram-positive d-alanine/d-alanyl carrier protein ligase, while the trio of proteins in the AlmEFG system forms a chemical pathway that resembles the division of labor in nonribosomal peptide synthetases.
PMCID: PMC4520716  PMID: 25068415

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