Upregulation of POC1A in lung adenocarcinoma promotes tumour progression and predicts poor prognosis.

Lung adenocarcinoma (LUAD) is characterized by a high incidence rate and mortality. Recently, POC1 centriolar protein A (POC1A) has emerged as a potential biomarker for various cancers, contributing to cancer onset and development. However, the association between POC1A and LUAD remains unexplored. We extracted The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) data sets to analyse the differential expression of POC1A and its relationship with clinical stage. Additionally, we performed diagnostic receiver operator characteristic (ROC) curve analysis and Kaplan-Meier (KM) survival analysis to assess the diagnostic and prognostic value of POC1A in LUAD. Furthermore, we investigated the correlation between POC1A expression and immune infiltration, tumour mutation burden (TMB), immune checkpoint expression and drug sensitivity. Finally, we verified POC1A expression using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Cell experiments were conducted to validate the effect of POC1A expression on the proliferation, migration and invasion of lung cancer cells. POC1A exhibited overexpression in most tumour tissues, and its overexpression in LUAD was significantly correlated with late-stage presentation and poor prognosis. The high POC1A expression group showed lower levels of immune infiltration but higher levels of immune checkpoint expression and TMB. Moreover, the high POC1A expression group demonstrated sensitivity to multiple drugs. In vitro experiments confirmed that POC1A knockdown led to decreased proliferation, migration, and invasion of lung cancer cells. Our findings suggest that POC1A may contribute to tumour development by modulating the cell cycle and immune cell infiltration. It also represents a potential therapeutic target and marker for the diagnosis and prognosis of LUAD.

Ciliopathies are responsible for short stature and insulin resistance: A systematic review of this clinical association regarding SOFT syndrome.

SOFT syndrome (Short stature-Onychodysplasia-Facial dysmorphism-hypoTrichosis) is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A encoding a centriolar protein. To refine the phenotypic spectrum of SOFT syndrome, recently shown to include metabolic features, we conducted a systematic review of all published cases (19 studies, including 42 patients). The SOFT tetrad affected only 24 patients (57%), while all cases presented with short stature from birth (median height: -5.5SDS([-8.5]-[-2.8])/adult height: 132.5 cm(103.5-148)), which was most often disproportionate (90.5%), with relative macrocephaly. Bone involvement resulted in short hands and feet (100%), brachydactyly (92.5%), metaphyseal (92%) or epiphyseal (84%) anomalies, and/or sacrum/pelvis hypoplasia (58%). Serum IGF-I was increased (median IGF-I level: + 2 SDS ([-0.5]-[+ 3])). Recombinant human growth hormone (rhGH) therapy was stopped for absence/poor growth response (7/9 patients, 78%) and/or hyperglycemia (4/9 patients, 45%). Among 11 patients evaluated, 10 (91%) presented with central distribution of fat (73%), clinical (64%) and/or biological insulin resistance (IR) (100%, median HOMA-IR: 18), dyslipidemia (80%), and hepatic steatosis (100%). Glucose tolerance abnormalities affected 58% of patients aged over 10 years. Patients harbored biallelic missense (52.4%) or truncating (45.2%) POC1A variants. Biallelic null variants, affecting 36% of patients, were less frequently associated with the SOFT tetrad (33% vs 70% respectively, p = 0.027) as compared to other variants, without difference in the prevalence of metabolic abnormalities. POC1A should be sequenced in children with short stature, altered glucose/insulin homeostasis and/or centripetal fat distribution. In patients with SOFT syndrome, rhGH treatment is not indicated, and IR-related complications should be regularly screened and monitored.PROSPERO registration: CRD42023460876.

SOFT syndrome with kohlschutter-Tonz syndrome.

We report a 2.2 year-old-boy, born of consanguineous marriage, referred for short stature, with history of neonatal death and skeletal deformities in his older sibling. Rhizo-mesomelic dwarfism was detected antenatally. Within 24 hours of birth, he developed multiple seizures. Examination revealed severe short stature, dolichocephaly, broad forehead, deep set eyes, low set ears, bulbous nose, small, irregular teeth, pointed chin, and triangular facies. He had rhizomelic shortening, stubby fingers, pes planus, and scanty hair. Neurological evaluation revealed ataxia, hypotonia, and global developmental delay. Skeletal survey radiograph revealed shallow acetabuli, short femurs and humerus, short, broad metacarpals and short cone-shaped phalanges with cupping of phalangeal bases. Clinical exome analysis revealed homozygous mutations involving the POC1A gene and the SLC13A5 gene responsible for SOFT syndrome and Kohlschutter-Tonz syndrome respectively, which were inherited from the parents. Both these syndromes are extremely rare, and their co-occurrence is being reported for the first time.

Clinical presentation and molecular characterization of a novel patient with variant POC1A-related syndrome.

Biallelic pathogenic variants in POC1A result in SOFT (Short-stature, Onychodysplasia, Facial-dysmorphism, and hypoTrichosis) and variant POC1A-related (vPOC1A) syndromes. The latter, nowadays described in only two unrelated subjects, is associated with a restricted spectrum of variants falling in exon 10, which is naturally skipped in a specific POC1A mRNA. The synthesis of an amount of a POC1A isoform from this transcript in individuals with vPOC1A syndrome has been believed as the likely explanation for such a genotype-phenotype correlation. Here, we illustrate the clinical and molecular findings in a woman who resulted to be compound heterozygous for a recurrent frameshift variant in exon 10 and a novel variant in exon 9 of POC1A. Phenotypic characteristics of this woman included severe hyperinsulinemic dyslipidemia, acanthosis nigricans, moderate growth restriction, and dysmorphisms. These manifestations overlap the clinical features of the two previously published individuals with vPOC1A syndrome. RT-PCR analysis on peripheral blood and subsequent sequencing of the obtained amplicons demonstrated a variety of POC1A alternative transcripts that resulted to be expressed in the proband, in the healthy mother, and in controls. We illustrate the possible consequences of the two POC1A identified variants in an attempt to explain pleiotropy in vPOC1A syndrome.

SOFT syndrome in a patient from Chile.

SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism caused by biallelic mutations in the POC1A gene. It is characterized by prenatal short stature, onychodysplasia, facial dysmorphism, hypotrichosis, and variable skeletal abnormalities including hypoplastic pelvis and sacrum, small hands, and cone-shaped epiphyses, as well as delayed bone age. To the best of our knowledge, only eight POC1A mutations have been reported in humans to date. We report a 7-year-old Chilean girl with SOFT syndrome arising from a novel POC1A mutation c. 649C>T, p.Arg217Trp. Although her clinical features were largely compatible with SOFT syndrome, hand X-ray examinations at 3.5 and 6 years unexpectedly showed normal bone age. Automated bone age determination was performed using image analysis software, BoneXpert. This case highlights the importance of the accumulation of patients with POC1A mutations to further elucidate the detailed clinical features of SOFT syndrome.

Two novel POC1A mutations in the primordial dwarfism, SOFT syndrome: Clinical homogeneity but also unreported malformations.

Primordial dwarfism encompasses rare conditions characterized by severe intrauterine growth retardation and growth deficiency throughout life. Recently, three POC1A mutations have been reported in six families with the primordial dwarfism, SOFT syndrome (Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis). Using a custom-designed Next-generation sequencing skeletal dysplasia panel, we have identified two novel homozygous POC1A mutations in two individuals with primordial dwarfism. The severe growth retardation and the facial profiles are strikingly similar between our patients and those described previously. However, one of our patients was diagnosed with severe foramen magnum stenosis and subglottic tracheal stenosis, malformations not previously associated with this syndrome. Our findings confirm that POC1A mutations cause SOFT syndrome and that mutations in this gene should be considered in patients with severe pre- and postnatal short stature, symmetric shortening of long bones, triangular facies, sparse hair and short, thickened distal phalanges.

Ciliopathy due to POC1A deficiency: clinical and metabolic features, and cellular modeling.

OBJECTIVE: SOFT syndrome (MIM#614813), denoting Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis, is a rare primordial dwarfism syndrome caused by biallelic variants in POC1A, encoding a centriolar protein. SOFT syndrome, characterized by severe growth failure of prenatal onset and dysmorphic features, was recently associated with insulin resistance. This study aims to further explore its endocrinological features and pathophysiological mechanisms. DESIGN/METHODS: We present clinical, biochemical, and genetic features of 2 unrelated patients carrying biallelic pathogenic POC1A variants. Cellular models of the disease were generated using patients' fibroblasts and POC1A-deleted human adipose stem cells. RESULTS: Both patients present with clinical features of SOFT syndrome, along with hyperinsulinemia, diabetes or glucose intolerance, hypertriglyceridemia, liver steatosis, and central fat distribution. They also display resistance to the effects of IGF-1. Cellular studies show that the lack of POC1A protein expression impairs ciliogenesis and adipocyte differentiation, induces cellular senescence, and leads to resistance to insulin and IGF-1. An altered subcellular localization of insulin receptors and, to a lesser extent, IGF1 receptors could also contribute to resistance to insulin and IGF1. CONCLUSIONS: Severe growth retardation, IGF-1 resistance, and centripetal fat repartition associated with insulin resistance-related metabolic abnormalities should be considered as typical features of SOFT syndrome caused by biallelic POC1A null variants. Adipocyte dysfunction and cellular senescence likely contribute to the metabolic consequences of POC1A deficiency. SOFT syndrome should be included within the group of monogenic ciliopathies with metabolic and adipose tissue involvement, which already encompasses Bardet-Biedl and Alström syndromes.

Pigmentary retinopathy with perivascular sparing in a SOFT syndrome patient with a novel homozygous splicing variant in POC1A gene.

PURPOSE: SOFT syndrome is an extremely rare inherited dwarfism syndrome. The syndrome has four major clinical manifestations: short stature, onychodysplasia, facial dysmorphism, and hypotrichosis. Herein, we report a unique case of a SOFT syndrome with findings of pigmentary retinopathy. METHODS: Case report. RESULTS: A 3-year boy was referred to our clinic for ophthalmologic examination from Genetic Diseases Diagnosis Center. In ophthalmic examination, anterior segment was normal bilaterally in biomicroscopy. Fundus examination revealed bilateral yellow-white punctate retinal pigment epithelium lesions located in the midperipheral retina. Macula optical coherence tomography was bilaterally normal. Whole exome sequencing (WES) analysis revealed a homozygous intronic splice site variant (c.103 + 1 G>T) in POC1A, hemizygous intronic splice site variant (c.459-5T>A) in TBX22, and a heterozygous missense variant (c.2254 C>T) in DDR2 genes. CONCLUSION: There is a limited number of reported cases with SOFT syndrome and, though retinal findings in SOFT syndrome have been reported in two cases previously, none were given in detail. According to our findings, perivascular and macula sparing midperipheral retina pigment epithelium changes could be observed in patients with SOFT syndrome.

Case Report: Identification of a rare nonsense mutation in the POC1A gene by NGS in a diabetes mellitus patient.

Objective: This study aimed to investigate the clinical and molecular biology of a patient with a type of diabetes mellitus caused by a mutation in the POC1A (OMIM number: 614783) gene and explore its pathogenesis and related characteristics. Methods: The patient was interviewed about his medical history and subjected to relevant examinations. Blood DNA samples were collected from the patient and his family members (parents) for trio whole-exome sequencing. Whole-exome sequencing was performed using the IDT xGen Exome Research Panel v1.0 whole-exome capture chip and sequenced using an Illumina NovaSeq 6,000 series sequencer (PE150); the sequencing coverage of the target sequence was not less than 99%. After systematic analysis and screening of the cloud platform for accurate diagnosis of genetic diseases, which integrated molecular biology annotation, biology, genetics, and clinical feature analysis, combined with a pathogenic mutation database, normal human genome database, and clinical feature database of 4,000 known genetic diseases, hundreds of thousands of gene variants were graded using the gene data analysis algorithm, a three-element grading system, and the American Society of Medical Genetics gene variant grading system. After polymerase chain reaction testing, the target sequence was verified by Sanger sequencing using an ABI3730 sequencer, and the verification result was obtained using sequence analysis software. Results: The patient had a peculiar face, a thin body, and a body mass index of 16.0 kg/m2. His fasting connecting peptide was 10.2 ug/L, his fasting insulin was 44 mIU/L, his fasting blood glucose was 10.5 mmol/L, and his glycosylated haemoglobin was 12.5%. After hospitalisation, the patient was given 0.75 g/d metformin tablets and 15 mg/d pioglitazone dispersible tablets, and his fasting blood glucose reduced to 9.2 mmol/L. After 48 U/L insulin treatment, the patient's fasting blood glucose was reduced to 8.5 mmol/L. Genetic screening revealed that there was a pathogenic variant at the POC1A gene locus and a cytosine-to-thymine mutation at the G81 locus, turning the Arg to a termination codon and shortening the POC1A protein from 359 amino acids (aa) to 80 aa. No mutation was detected in the patient's parents' POC1A gene loci. Conclusion: The patient's diabetes was caused by a POC1A gene mutation at the G81 locus, which is rarely reported in the clinic. The specific manifestations of this mutation need to be further investigated.

POC1A, prognostic biomarker of immunosuppressive microenvironment in cancer.

POC1 centriolar protein A (POC1A) effect in pan-cancer remains uncertain. The POC1A expression in normal and tumor tissues underwent analysis in this study utilizing data from the Genotype-Tissue Expression (GTEx) project and the Cancer Genome Atlas (TCGA) database. POC1A prognostic value and clinicopathological features were assessed utilizing the TCGA cohort. The relationship between immunological cell infiltration and POC1A of TCGA samples downloaded from TIMER2 and ImmuCellAI databases were observed. The relation between POC1A and immunological checkpoints genes, microsatellite instability (MSI) as well as tumor mutation burden (TMB) was also evaluated. Additionally, gene set enrichment analysis (GSEA) was utilized for exploring POC1A potential molecular mechanism in pan-cancer. In almost all 33 tumors, POCA1 showed a high expression. In most cases, high POC1A expression was linked significantly with a poor prognosis. Additionally, Tumor immune infiltration and tumors microenvironment were correlated with the expression of POC1A. In addition, TMB and MSI, as well as immune checkpoint genes in pan-cancer, were related to POC1A expression. In GSEA analysis, POC1A is implicated in cell cycle and immune-related pathways. These results might elucidate the crucial roles of POC1A in pan-cancer as a prognostic biomarker and immunotherapy target.

Identification of SOFT syndrome caused by a pathogenic homozygous splicing variant of POC1A: a case report.

BACKGROUND: Pathogenic variants in POC1A led to SOFT syndrome and variant POC1A-related (vPOC1A) syndrome. SOFT syndrome is a rare primordial dwarfism condition characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis.The main clinical differences between SOFT and vPOC1A syndrome include dyslipidemia with insulin resistance and acanthosis nigricans. To our knowledge, this is the first report of a SOFT syndrome patient diagnosed with a homozygous splicing variant, which could help to extend our understanding of the genotypic and phenotypic information of the disease. CASE PRESENTATION: We reported a seven-year-old boy with SOFT syndrome. The patient presented symmetrical short stature and facial features, including prominent forehead, inverted triangular face, epicanthal fold, small teeth and enlarged ears. Laboratory tests displayed mild insulin resistance. Whole-exome sequencing (WES) led to the identification of a homozygous splicing variant (c.981+1G>A) in POC1A gene of the patient, which was inherited from his heterozygous parents confirmed by Sanger sequencing. Further transcriptional experiments of the splicing variant revealed aberrant percentage of exon 9 skipping transcripts. CONCLUSIONS: This is the firstly reported case of a SOFT syndrome patient with a novel homozygous splicing variant and detailed delineation of the aberrant transcript in proband and carrier of the variant in Chinese. Our study enriched mutational spectrum of POC1A which could help in further genetic diagnosis and counselling of SOFT syndrome patients.

POC1A acts as a promising prognostic biomarker associated with high tumor immune cell infiltration in gastric cancer.

The effect of POC1 centriolar protein A (POC1A) on gastric cancer (GC) has not been clearly defined. In this study, POC1A expression and clinical information in patients with GC were analyzed. Multiple databases were used to investigate the genes that were co-expressed with POC1A and genes whose changes co-occurred with genetic alternations of POC1A. Moreover, the TISIDB and TIMER databases were used to analyze immune infiltration. The GSE54129 GC dataset and LASSO regression model (tumor vs. normal) were employed, and 6 significant differentially expressed genes (LAMP5, CEBPB, ARMC9, PAOX, VMP1, POC1A) were identified. POC1A was selected for its high expression in adjacent tissues, which was confirmed with IHC. High POC1A expression was related to better overall and recurrence-free survival. GO and KEGG analyses demonstrated that POC1A may regulate the cell cycle, DNA replication and cell growth. Furthermore, POC1A was found to be correlated with immune infiltration levels in GC according to the TISIDB and TIMER databases. These findings indicate that POC1A acts as a tumor suppressor in GC by regulating the cell cycle and cell growth. In addition, POC1A preferentially regulates the immune infiltration of GC via several immune genes. However, the specific mechanism requires further study.

Identification of Cellular Pathogenicity Markers for SIL1 Mutations Linked to Marinesco-Sjögren Syndrome.

Background and objective: Recessive mutations in the SIL1 gene cause Marinesco-Sjögren syndrome (MSS), a rare neuropediatric disorder. MSS-patients typically present with congenital cataracts, intellectual disability, cerebellar ataxia and progressive vacuolar myopathy. However, atypical clinical presentations associated with SIL1 mutations have been described over the last years; compound heterozygosity of SIL1 missense mutations even resulted in a phenotype not fulfilling the clinical diagnostic criteria of MSS. Thus, a read-out system to evaluate reliably the pathogenicity of amino acid changes in SIL1 is needed. Here, we aim to provide suitable cellular biomarkers enabling the robust evaluation of pathogenicity of SIL1 mutations. Methods: Five SIL1 variants including one polymorphism (p.K132Q), three known pathogenic mutations (p.V231_I232del, p.G312R, and p.L457P) and one ambiguous missense variant (p.R92W) were studied along with the wild-type proteins in Hek293 in vitro models by cell biological assays, immunoprecipitation, immunoblotting, and immunofluorescence as well as electron microscopy. Moreover, the SIL1-interactomes were interrogated by tandem-affinity-purification and subsequent mass spectrometry. Results: Our combined studies confirmed the pathogenicity of p.V231_I232del, p.G312R, and p.L457P by showing instability of the proteins as well as tendency to form aggregates. This observation is in line with altered structure of the ER-Golgi system and vacuole formation upon expression of these pathogenic SIL1-mutants as well as the presence of oxidative or ER-stress. Reduced cellular fitness along with abnormal mitochondrial architecture could also be observed. Notably, both the polymorphic p.K132Q and the ambiguous p.R92W variants did not elicit such alterations. Study of the SIL1-interactome identified POC1A as a novel binding partner of wild-type SIL1; the interaction is disrupted upon the presence of pathogenic mutants but not influenced by the presence of benign variants. Disrupted SIL1-POC1A interaction is associated with centrosome disintegration. Conclusions: We developed a combination of cellular outcome measures to evaluate the pathogenicity of SIL1 variants in suitable in vitro models and demonstrated that the p. R92W missense variant is a polymorphism rather than a pathogenic mutation leading to MSS.

Truncation of POC1A associated with short stature and extreme insulin resistance.

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health.