Mitochondrial disease and endocrine dysfunction

Mitochondria are critical organelles for endocrine health; steroid hormone biosynthesis occurs in these organelles and they provide energy in the form of ATP for hormone production and trafficking. Mitochondrial diseases are multisystem disorders that feature defective oxidative phosphorylation, and are characterized by enormous clinical, biochemical and genetic heterogeneity. To date, mitochondrial diseases have been found to result from >250 monogenic defects encoded across two genomes: the nuclear genome and the ancient circular mitochondrial genome located within mitochondria themselves. Endocrine dysfunction is often observed in genetic mitochondrial diseases and reflects decreased intracellular production or extracellular secretion of hormones. Diabetes mellitus is the most frequently described endocrine disturbance in patients with inherited mitochondrial diseases, but other endocrine manifestations in these patients can include growth hormone deficiency, hypogonadism, adrenal dysfunction, hypoparathyroidism and thyroid disease. Although mitochondrial endocrine dysfunction frequently occurs in the context of multisystem disease, some mitochondrial disorders are characterized by isolated endocrine involvement. Furthermore, additional monogenic mitochondrial endocrine diseases are anticipated to be revealed by the application of genome-wide next-generation sequencing approaches in the future. Understanding the mitochondrial basis of endocrine disturbance is key to developing innovative therapies for patients with mitochondrial diseases

Renal magnesium handling: New insights in understanding old problems

Many sharp-eyed readers have pointed out to us that in the photo next to the article about yams in Ghana (Spore 87, June 2000, page 8), the woman had put all her cassava in one basket, and not the yams she planned to use. Point taken. Whatever you want to point out, point to or point at, your letters, faxes and emails are always welcome at the Spore address in the box on the right. Write now.MailboxMany sharp-eyed readers have pointed out to us that in the photo next to the article about yams in Ghana (Spore 87, June 2000, page 8), the woman had put all her cassava in one basket, and not the yams she planned to use. Point taken...

Hereditary kidney diseases associated with hypomagnesemia

In the kidney, a set of proteins expressed in the epithelial cells of the thick ascending loop of Henle and the distal convoluted tubule directly or indirectly play important roles in the regulation of serum magnesium levels. Magnesium reabsorption in the thick ascending loop of Henle occurs through a passive paracellular pathway, while in the distal convoluted tubule, the final magnesium concentration is established through an active transcellular pathway. The players involved in magnesium reabsorption include proteins with diverse functions including tight junction proteins, cation and anion channels, sodium chloride cotransporter, calcium-sensing receptor, epidermal growth factor, cyclin M2, sodium potassium adenosine triphosphatase subunits, transcription factors, a serine protease, and proteins involved in mitochondrial function. Mutations in the genes that encode these proteins impair their function and cause different rare diseases associated with hypomagnesemia, which may lead to muscle cramps, fatigue, epileptic seizures, intellectual disability, cardiac arrhythmias, and chronic kidney disease. The purpose of this review is to describe the clinical and genetic characteristics of these hereditary kidney diseases and the current research findings on the pathophysiological basis of these diseases

Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome : case report and review of the literature

Galloway-Mowat syndrome (GAMOS) is a rare autosomal recessive disorder characterized by early-onset nephrotic syndrome and microcephaly with brain anomalies. WDR73 pathogenic variants were described as the first genetic cause of GAMOS and, very recently, four novel causative genes, OSGEP, LAGE3, TP53RK, and TPRKB, have been identified. We present the clinical and genetic characteristics of two unrelated infants with clinical suspicion of GAMOS who were born from consanguineous parents. Both patients showed a similar clinical presentation, with early-onset nephrotic syndrome, microcephaly, brain atrophy, developmental delay, axial hypotonia, and early fatality. We identified two novel likely disease-causing variants in the OSGEP gene. These two cases, in conjunction with the findings of a literature review, indicate that OSGEP pathogenic variants are associated with an earlier onset of nephrotic syndrome and shorter life expectancy than WDR73 pathogenic variants. Our findings expand the spectrum of pathogenic variants in the OSGEP gene and, taken in conjunction with the results of the literature review, suggest that the OSGEP gene should be considered the main known monogenic cause of GAMOS. Early genetic diagnosis of GAMOS is of paramount importance for genetic counseling and family planning

Clinical characterization, genetic screening and genotype-phenotype associations in cerebellar and brainstem congenital defects

2018 - 2019Cerebellar and brainstem congenital defects (CBCDs) represent a wide spectrum of malformative disorders resulting from abnormal development of midbrain-hindbrain and characterised by high clinical and genetic heterogeneity. Due to the uncommonness of these conditions and the substantial under-recognition on brain imaging studies, limited information is available on their prevalence, genetic causes, natural history, and genotype-phenotype associations. Such a contingency of factors leads to uncertain prognosis and wrong counselling. .. [edited by the Author]XXXII cicl

Identification of FAM20C binding proteins

FAM20 (family with sequence similarity 20) members in humans consist of FAM20A, FAM20B and FAM20C. The mutations of FAM20A in humans lead to Amelogenesis Imperfecta (AI), gingival hyperplasia and enamel renal syndrome (ERS) in humans. Mutations of FAM20B in Danio rerio result in decreased cartilage matrix production and skeletal defects. Mutations in FAM20C leads to neonatal lethal osteosclerotic bone dysplasia in humans, known as Raine syndrome. One of the mutants is FAM20C-D478A. FAM20C intracellularly functions as a Golgi casein kinase. It phosphorylates secretory pathway proteins within S-x-E motif (where S is Ser, X is any amino acid, and E is Glu). Extracellular role of FAM20C has also been suggested as a growth and differentiation factor, and the exogenous FAM20C treatment accelerates MC3T3-E1 osteoblast differentiation and mineralization in vitro. The first purpose of this study was to purify FAM20C protein. HEK 293 cells were transfected with FAM20C expression vectors, cell clones that overexpress FAM20C were isolated and FAM20C protein was collected and purified. The Western blot results of purified FAM20C showed higher bands, around 100 kDa and 170 kDa, than expected molecular weight, 66 kDa. Post-translational modification was thought to be the possible reason. Therefore, the second purpose was to find binding proteins of FAM20C by mass spectrometry protein identification analysis to check if FAM20C has other post-modifications, such as glycosylation. FAM20C-WT and FAM20C-D478A proteins were chosen to perform the study since FAM20C-D478A was investigated in previous studies of Golgi casein kinase, FAM20C, and was found to have no kinase activity. In this study, periostin was identified to bind to FAM20C and the binding of these 2 proteins was confirmed by immunoprecipitation and Western blot analysis. Since FAM20C functions as a secretory kinase, it is suggested that periostin may be a substrate for FAM20C kinase. Further investigation is needed to determine the presence of phosphorylation in periostin and its role in periosteum and periodontal ligament

Establishment of urinary exosome-like vesicles isolation protocol for FHHNC patients and evaluation of different exosomal RNA extraction methods

Molecular and cellular pathophysiological events occurring in the majority of rare kidney diseases remain to be elucidated. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in either CLDN16 or CLDN19 genes. This disease is characterized by massive urinary wasting of magnesium and calcium, osmosis deregulation and polyuria. Patients with p.G20D homozygous mutation in CLDN19 gene exhibit different progression to kidney failure suggesting that beyond the pathogenic mutation itself, other molecular events are favoring disease progression. Due to the fact that biopsy is not clinically indicated in these patients, urinary exosome-like vesicles (uEVs) can be envisioned as a valuable non-invasive source of information of events occurring in the kidney. Exosome research has increased notably to identify novel disease biomarkers but there is no consensus standardized protocols for uEVs isolation in patients with polyuria. For this reason, this work was aimed to evaluate and refine different uEVs isolation methods based on differential centrifugation, the gold standard method. Characterization by NTA, cryo-TEM and immunoblotting techniques identified the most appropriate protocol to obtain the highest yield and purest uEVs enriched fraction possible from urine control samples and FHHNC patients. Moreover, we tested five different RNA extraction methods and evaluated the miRNA expression pattern by qRT-PCR. In summary, we have standardized the conditions to proceed with the identification of differentially expressed miRNAs in uEVs of FHHNC patients, or other renal diseases characterized by polyuria