Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel FAM20C Variant.
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SUBMITTER: Eras N
PROVIDER: S-EPMC8216011 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
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Nonlethal Raine Syndrome in a Newborn Boy Caused by a Novel <i>FAM20C</i> Variant.
Molecular syndromology 20210322 3
Raine syndrome (RS) is a rare genetic disorder characterized by osteosclerotic bone dysplasia caused by a homozygous mutation, compound heterozygous mutation, or microdeletion in the <i>FAM20C</i> gene. In the present study, the MiSeq next-generation sequencing platform was used to perform the <i>FAM20C</i> gene sequence analysis. A novel homozygous variant c.1255T>C (p.W419R) in the <i>FAM20C</i> gene was diagnosed, and a nonlethal RS phenotype was confirmed, thus contributing to the expansion ...[more]
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Project description:Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs.
| S-EPMC7073523 | biostudies-literature
Project description:FAM20C is a gene coding for a protein kinase that targets S-X-E/pS motifs on different phosphoproteins belonging to diverse tissues. Pathogenic variants of FAM20C are responsible for Raine syndrome (RS), initially described as a lethal and congenital osteosclerotic dysplasia characterized by generalized atherosclerosis with periosteal bone formation, characteristic facial dysmorphisms and intracerebral calcifications. The aim of this review is to give an overview of targets and variants of FAM20C as well as RS aspects. We performed a wide phenotypic review focusing on clinical aspects and differences between all lethal (LRS) and non-lethal (NLRS) reported cases, besides the FAM20C pathogenic variant description for each. As new targets of FAM20C kinase have been identified, we reviewed FAM20C targets and their functions in bone and other tissues, with emphasis on novel targets not previously considered. We found the classic lethal and milder non-lethal phenotypes. The milder phenotype is defined by a large spectrum ranging from osteonecrosis to osteosclerosis with additional congenital defects or intellectual disability in some cases. We discuss our current understanding of FAM20C deficiency, its mechanism in RS through classic FAM20C targets in bone tissue and its potential biological relevance through novel targets in non-bone tissues.
| S-EPMC8348777 | biostudies-literature
Project description:FAM20C (family with sequence similarity 20-member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. FAM20C loss-of-function mutations cause Raine syndrome in humans, characterized by generalized osteosclerosis, distinctive craniofacial dysmorphism, along with extensive intracranial calcification. Our previous studies revealed that inactivation of Fam20c in mice led to hypophosphatemic rickets. In this study, we examined the expression of Fam20c in the mouse brain and investigated brain calcification in Fam20c-deficient mice. Reverse transcription polymerase chain reaction (RT-PCR), Western-blotting and in situ hybridization analyses demonstrated the broad expression of Fam20c in the mouse brain tissue. X-ray and histological analyses showed that the global deletion of Fam20c (mediated by Sox2-cre) resulted in brain calcification in mice after postnatal 3 months and that the calcifications were bilaterally distributed within the brain. There was mild perifocal microgliosis as well as astrogliosis around calcospherites. The calcifications were first observed in the thalamus, and later in the forebrain and hindbrain. Furthermore, brain-specific deletion (mediated by Nestin-cre) of Fam20c in mice also led to cerebral calcification at an older age (postnatal 6 months), but no obvious skeletal or dental defects. Our results suggest that the local loss of FAM20C function in the brain may directly account for intracranial calcification. We propose that FAM20C plays an essential role in maintaining normal brain homeostasis and preventing ectopic brain calcification.
| S-EPMC11795667 | biostudies-literature
Project description:BackgroundBi-allelic mutations in FAM20C gene are known to cause a rare genetic disorder- Raine syndrome (RS). The FAM20C protein binds calcium and phosphorylates proteins involved in biomineralization of bones and teeth. RS is recognized as an osteosclerotic bone dysplasia. It is characterized by distinctive facial features, generalized osteosclerosis and respiratory insufficiency along with periosteal bone formation. RS is typically described as being an aggressive skeletal dysplasia with death in the neonatal period or early infancy. However, in the recent past an increasing number of individuals having an extended life span along with a highly heterogeneous phenotype has led to classifying RS into short and extended lifespan categories.Case presentationWe report a case of RS with antenatal fractures, facial dysmorphism and osteosclerosis without significant respiratory manifestations. The child has a relatively extended lifespan, whereby she died at 17-months of age. Clinical exome sequencing revealed a previously known, homozygous, nonsense variant c.1680C > A (p.Cys560Ter) in exon 10 of FAM20C. Whilst the variant was initially classified as a variant of uncertain significance (VUS), through the latest release of gnomAD and GTEx data, this was subsequently re-classified as likely pathogenic. Furthermore, segregation analysis showed both parents to be carriers. In contrast, a previously reported case with the same variant had polyhydramnios, complex facial abnormalities and bright echogenic brain parenchyma with oval shaped skull and anterior flattening at 26 weeks of gestation.ConclusionThe variant identified has been previously reported as a VUS. The present case provides further evidence towards the pathogenicity of the variant. A plausible genotype-phenotype correlation based on the location of the variant has been verified, wherein the position of a nonsense variant in the terminal exon of FAM20C gene, could have had a partial effect on the protein function, thereby resulting in a relatively milder phenotype and extended lifespan. Furthermore, the vast phenotypic variation on clinical comparison current case and a previously reported case, despite having the same genotype, could suggest an oligogenic effect and/ or environmental influence.
| S-EPMC7936445 | biostudies-literature
Project description:Raine syndrome is caused by mutations in FAM20C, which had been reported to encode a secreted component of bone and teeth. We found that FAM20C encodes a Golgi-localized protein kinase, distantly related to the Golgi-localized kinase Four-jointed. Drosophila also encode a Golgi-localized protein kinase closely related to FAM20C. We show that FAM20C can phosphorylate secreted phosphoproteins, including both Casein and members of the SIBLING protein family, which modulate biomineralization, and we find that FAM20C phosphorylates a biologically active peptide at amino acids essential for inhibition of biomineralization. We also identify autophosphorylation of FAM20C, and characterize parameters of FAM20C's kinase activity, including its Km, pH and cation dependence, and substrate specificity. The biochemical properties of FAM20C match those of an enzymatic activity known as Golgi casein kinase. Introduction of point mutations identified in Raine syndrome patients into recombinant FAM20C impairs its normal localization and kinase activity. Our results identify FAM20C as a kinase for secreted phosphoproteins and establish a biochemical basis for Raine syndrome.
| S-EPMC3416761 | biostudies-literature
Project description:BackgroundInactivation or mutations of FAM20C causes human Raine Syndrome, which manifests as lethal osteosclerosis bone dysplasia or non-lethal hypophosphatemia rickets. However, it is only hypophosphatemia rickets that was reported in the mice with Fam20c deletion or mutations. To further investigate the local and global impacts of Fam20c mutation, we constructed a knock-in allele carrying Fam20c mutation (D446N) found in the non-lethal Raine Syndrome. The Fam20cD446N allele replaced the WT Fam20c by 3.6Kb Col1a1-Cre to get the conditional knock-in mice, and by Hprt-cre to get conventional knock-in mice, respectively.ResultsThe radiology, serum biochemistry and immunohistochemistry indicated that all conditional and most conventional Fam20cD446N knock-in mice displayed hypophosphatemic rickets with the increased Fgf23 and deceased Dmp1 expression, which survived to adulthood. However, a few conventional Fam20cD446N knock-in mice died before weaning with the osteosclerotic X-ray radiography, though micro-CT assay displayed a reduced mineral density and increased porosity in the osteosclerotic tibia. Our results suggested that hypophosphatemia rickets was the predominant phenotype in both conditional and conventional Fam20c deficient mice, while the lethal osteosclerotic phenotype occasionally took place in the conventional Fam20c mutant mice.ConclusionThis finding also implicated that the osteosclerotic features resulting from Fam20c deficiency could be a semblance on the basis of rickets, which is most likely triggered by the alterations in the systems other than skeleton.
| S-EPMC11697891 | biostudies-literature
Project description:FAM20C (family with sequence similarity 20, member C) is a serine/threonine-specific protein kinase that is ubiquitously expressed and mainly associated with biomineralization and phosphatemia regulation. It is mostly known due to pathogenic variants causing its deficiency, which results in Raine syndrome (RNS), a sclerosing bone dysplasia with hypophosphatemia. The phenotype is recognized by the skeletal features, which are related to hypophosphorylation of different FAM20C bone-target proteins. However, FAM20C has many targets, including brain proteins and the cerebrospinal fluid phosphoproteome. Individuals with RNS can have developmental delay, intellectual disability, seizures, and structural brain defects, but little is known about FAM20C brain-target-protein dysregulation or about a potential pathogenesis associated with neurologic features. In order to identify the potential FAM20C actions on the brain, an in silico analysis was conducted. Structural and functional defects reported in RNS were described; FAM20C targets and interactors were identified, including their brain expression. Gene ontology of molecular processes, function, and components was completed for these targets, as well as for potential involved signaling pathways and diseases. The BioGRID and Human Protein Atlas databases, the Gorilla tool, and the PANTHER and DisGeNET databases were used. Results show that genes with high expression in the brain are involved in cholesterol and lipoprotein processes, plus axo-dendritic transport and the neuron part. These results could highlight some proteins involved in the neurologic pathogenesis of RNS.
| S-EPMC10219294 | biostudies-literature
Project description:Raine syndrome is a congenital disorder caused by biallelic mutations in the FAM20C gene. While most diagnosed cases of the syndrome are lethal in the first few months of life, there are also reports of non-lethal cases with Raine syndrome. The characteristic of this syndrome is typical facial dysmorphism and generalized osteosclerosis, as well as possible intracranial calcification, hearing loss, and seizures. We report a case of a 4-day-old patient at the time of examination, born with a distinct facial dysmorphism, short neck, narrow chest, and curved tibia. The parents, affirmative gypsy and non-consanguineous, had a previous male child born with the same phenotype who died at 4 months old. The computed tomography scan revealed choanal atresia, while transfontanelar ultrasound showed hypoplasia of the frontal and temporal lobes, corpus callosum dysgenesis, and multiple areas of intracranial hyperechogenicity. The chest X-Ray revealed generalized increased bone density. A skeletal disorders gene panel was performed which identified two variants in the FAM20C gene: a pathogenic variant c.1291C>T (p.Gln431*) and a likely pathogenic variant (c.1135G>A) (p.Gly379Arg), confirming the clinical diagnosis. The parents were also tested, and each was found to carry one of the variants. The particularity of this case is the severe phenotype in a compound heterozygous case that consists of FAM20C c.1291C>T (p.Gln431*) variant that has recently been reported in the literature. Also, our case is one of the few compound-heterozygous mutations in the FAM20C gene that has been described in a non-consanguineous marriage.
| S-EPMC10171555 | biostudies-literature
Project description:BackgroundRaine syndrome (RS) is a rare autosomal recessive bone dysplasia typified by osteosclerosis and dysmorphic facies due to FAM20C mutations. Initially reported as lethal in infancy, survival is possible into adulthood. We describe the molecular analysis and clinical phenotypes of five individuals from two consanguineous Brazilian families with attenuated Raine Syndrome with previously unreported features.MethodsThe medical and dental clinical records were reviewed. Extracted deciduous and permanent teeth as well as oral soft tissues were analysed. Whole exome sequencing was undertaken and FAM20C cDNA sequenced in family 1.ResultsFamily 1 included 3 siblings with hypoplastic Amelogenesis Imperfecta (AI) (inherited abnormal dental enamel formation). Mild facial dysmorphism was noted in the absence of other obvious skeletal or growth abnormalities. A mild hypophosphataemia and soft tissue ectopic mineralization were present. A homozygous FAM20C donor splice site mutation (c.784 + 5 g > c) was identified which led to abnormal cDNA sequence. Family 2 included 2 siblings with hypoplastic AI and tooth dentine abnormalities as part of a more obvious syndrome with facial dysmorphism. There was hypophosphataemia, soft tissue ectopic mineralization, but no osteosclerosis. A homozygous missense mutation in FAM20C (c.1487C > T; p.P496L) was identified.ConclusionsThe clinical phenotype of non-lethal Raine Syndrome is more variable, including between affected siblings, than previously described and an adverse impact on bone growth and health may not be a prominent feature. By contrast, a profound failure of dental enamel formation leading to a distinctive hypoplastic AI in all teeth should alert clinicians to the possibility of FAM20C mutations.
| S-EPMC4422040 | biostudies-literature
Project description:BackgroundCornelia de Lange syndrome (CdLS) is mainly characterized by specific facial features, growth retardation, and bone deformities. Seven genes reportedly cause CdLS. Recent research has reported that loss-of-function variants affecting MAU2, which encodes a regulator of the cohesin complex, can cause CdLS. Thus far, only one MAU2-CdLS case has been reported worldwide.MethodsWe detected a novel variant in MAU2 gene, NM_015329, c.526C>T (p.Arg176Trp) in a Chinese patient with CdLS, constructed a plasmid for in vitro transcriptional and protein level analysis, and analyzed the interaction between the MAU2/NIPBL complex using molecular dynamics (MD).ResultsThe results showed that the level of the exogenous MAU2 mutant protein was significantly reduced compared with that of the exogenous wild-type protein. However, MD analysis predicted an increased binding free energy between the MAU2 and NIPBL proteins that may impact the structural stability of the complex.ConclusionWe investigated a MAU2-CdLS case in a Chinese family, which strengthens the association between MAU2 variants and CdLS phenotypes. We therefore propose that MAU2 be included in the CdLS gene screening list.
| S-EPMC10767608 | biostudies-literature