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Calcified Tissue International Apr 2023Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of...
INTRODUCTION
Progressive osseous heteroplasia (POH) is a rare, debilitating disorder characterized by heterotopic ossification in the skin and muscles, resulting in contractures of the joints and progressive loss of function. While 60-70% of the POH patients have paternally inherited, inactivating pathogenic variants in GNAS, the remaining 30-40% have no known etiology. FAM111B pathogenic variants, located on chromosome 11q12.1, cause POIKTMP (hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis), a very rare, autosomal-dominant disorder with high frequency of de novo missense pathogenic variants, which affects multiple tissues and organs, causing extensive fibrosis and muscle adiposis, though the exact mechanism is unknown. To our knowledge, there are no reports of FAM111B associated with POH. We describe the first case of POH phenotype associated with a novel de novo frameshift pathogenic variant in the FAM111B and present an analysis of the protein structure and function caused by this genomic disruption.
CASE
A 15-year-old African-American male presented with generalized calcific nodules, progressive contractures, and muscle weakness leading to immobility, beginning at 6 years of age. Cutaneous examination showed generalized hard nodules varying from small to plaque-like ulcerated erupted skin lesions. Biochemical evaluation revealed 25(OH) vitamin D insufficiency (20 ng/mL), and normal levels of parathyroid hormone, FGF-23, alkaline phosphatase, calcium, and phosphorus. Skeletal survey radiographs and computed tomography (CT) of the chest, abdomen, and pelvis showed extensive soft tissue and muscle heterotopic ossifications involving shoulders, axillae, trunk, abdomen, pelvis, upper and lower extremities, in a clumped, conglomerate distribution within muscle, subcutaneous fat, and in some areas extending to the skin. There was no pulmonary fibrosis on the chest CT. The clinical and radiographic findings were most consistent with POH. A trio-clinical exome sequencing revealed a de novo heterozygous likely pathogenic variant in the FAM111B (OMIM # 615584) (c.1462delT [p.Cys488Valfs*21]). The resulted frameshift change in exon 4 replaced C-terminal region with 21 alternative amino acids. Multiple, previously reported disease-associated variants appear to localize within the trypsin-like cysteine/serine peptidase domain in which this variant occurs, supporting the functional significance of this region, though none have been previously reported to be associated with POH phenotype. Our 3D protein modeling showed obliteration of predicted protein folding and structure, and elimination of the zinc-binding domain, likely severely affecting protein function.
CONCLUSION
This is the first case of POH phenotype associated with a novel de novo pathogenic frameshift variant in FAM111B. Whether the frameshift change in FAM111B predicts POH remains unclear. Further evaluations are necessary to fully elucidate this finding and the potential role and mechanism by which the FAM111B variants contributes to POH phenotype.
Topics: Male; Humans; GTP-Binding Protein alpha Subunits, Gs; Ossification, Heterotopic; Phenotype; Contracture; Fibrosis; Cell Cycle Proteins
PubMed: 36575358
DOI: 10.1007/s00223-022-01053-0 -
Rheumatology (Oxford, England) May 2020
PubMed: 32415769
DOI: 10.1093/rheumatology/keaa236 -
Indian Journal of Dermatology 2020Poikilodermatous mycosis fungoides (PMF) is a rare clinical variant of early-stage mycosis fungoides with peculiar histological features and with low risk of disease...
Poikilodermatous mycosis fungoides (PMF) is a rare clinical variant of early-stage mycosis fungoides with peculiar histological features and with low risk of disease progression. Since poikiloderma can coexist with classical mycosis fungoides lesions, PMF can only be considered when poikilodermatous lesions are predominant (>50% of lesions). We here report one such rare case of PMF with poikilodermatous lesions covering almost 70% of the body surface and with characteristic clinical, histopathological, dermoscopic, and immunohistochemical findings.
PubMed: 33165346
DOI: 10.4103/ijd.IJD_145_19 -
PLoS Genetics Jul 2019Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, juvenile cataracts,...
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by skin rash (poikiloderma), skeletal dysplasia, small stature, juvenile cataracts, sparse or absent hair, and predisposition to specific malignancies such as osteosarcoma and hematological neoplasms. RTS is caused by germ-line mutations in RECQL4, a RecQ helicase family member. In vitro studies have identified functions for the ATP-dependent helicase of RECQL4. However, its specific role in vivo remains unclear. To determine the physiological requirement and the biological functions of Recql4 helicase activity, we generated mice with an ATP-binding-deficient knock-in mutation (Recql4K525A). Recql4K525A/K525A mice were strikingly normal in terms of embryonic development, body weight, hematopoiesis, B and T cell development, and physiological DNA damage repair. However, mice bearing two distinct truncating mutations Recql4G522Efs and Recql4R347*, that abolished not only the helicase but also the C-terminal domain, developed a profound bone marrow failure and decrease in survival similar to a Recql4 null allele. These results demonstrate that the ATP-dependent helicase activity of Recql4 is not essential for its physiological functions and that other domains might contribute to this phenotype. Future studies need to be performed to elucidate the complex interactions of RECQL4 domains and its contribution to the development of RTS.
Topics: Adenosine Triphosphate; Animals; B-Lymphocytes; Binding Sites; Body Weight; DNA Damage; Disease Models, Animal; Embryonic Development; Gene Knock-In Techniques; Hematopoiesis; Humans; Mice; Phenotype; Protein Domains; RecQ Helicases; Rothmund-Thomson Syndrome; T-Lymphocytes
PubMed: 31276497
DOI: 10.1371/journal.pgen.1008266 -
American Journal of Medical Genetics.... Jan 2023Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse...
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder.
Topics: Female; Humans; Rothmund-Thomson Syndrome; Constriction, Pathologic; RecQ Helicases; Osteosarcoma; Mutation; Puberty, Precocious; Bone Neoplasms
PubMed: 36164748
DOI: 10.1002/ajmg.a.62980 -
Frontiers in Genetics 2023
Commentary: Case report: Hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) presenting with liver cirrhosis and steroid-responsive interstitial pneumonia.
PubMed: 38188503
DOI: 10.3389/fgene.2023.1255807 -
European Journal of Dermatology : EJD Jun 2020Dermatomyositis (DM) is a group of autoimmune diseases characterized by a variable degree of skin symptoms and myopathy. An amyopathic form of DM (ADM) has been...
Dermatomyositis (DM) is a group of autoimmune diseases characterized by a variable degree of skin symptoms and myopathy. An amyopathic form of DM (ADM) has been described, and more recently, an anti-TIF-1 gamma-positive subtype, characterized by poikiloderma and associated with a relatively high risk of cancer. To characterise a cohort of DM patients. A cohort of 29 DM patients was followed between January 2004 and March 2019, and investigated for clinical characteristics, pathological features based on electromyography and MRI, laboratory data, and auto-antibody profile. Based on the investigations, DM was shown to be heterogeneous. However, we identified a subgroup of anti-TIF-1 gamma-positive patients who all shared heliotrope erythema. Furthermore, we observed a positive correlation between serum glutamicoxaloacetic transaminase (GOT) and creatine kinase (CK) concentrations in patients with anti-TIF-1 gamma antibodies, which is not found in patients with anti-MDA-5 antibodies. Based on the findings of this study, we propose an update of the Sontheimer et al. diagnostic criteria to improve the sensitivity of diagnosis for ADM. In addition, we describe a significant association between serum GOT and CK levels in DM patients with anti-TIF-1 gamma antibodies, and further highlight the significance of heliotrope rash as a clinical hallmark for this particular subset of patients.
Topics: Alanine Transaminase; Antibodies, Antinuclear; Aspartate Aminotransferases; Biopsy; Creatine Kinase; Dermatomyositis; Electromyography; Erythema; Female; Humans; Interferon-Induced Helicase, IFIH1; L-Lactate Dehydrogenase; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Paraneoplastic Syndromes; Photosensitivity Disorders; Skin; Transcription Factors
PubMed: 32666928
DOI: 10.1684/ejd.2020.3766 -
International Journal of General... 2023FAM111B (FAM111 trypsin-like peptidase B) gene mutations have been linked to a hereditary fibrosing poikiloderma disorder known to cause poikiloderma, tendon...
INTRODUCTION
FAM111B (FAM111 trypsin-like peptidase B) gene mutations have been linked to a hereditary fibrosing poikiloderma disorder known to cause poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP). Overexpression of FAM111B has been associated with an increased risk of certain cancers with a poor prognosis, although the relationship between FAM111B and other tumors is still unclear, and the molecular mechanism of its action is not fully understood.
METHODS
We investigated the biological functions of FAM111B in 33 solid tumors using multi-omics data. We further recruited 109 gastric cancer (GC) patients for a clinical cohort study to confirm the effect of FAM111B on early tumor recurrence. Furthermore, we assessed the role of FAM111B in GC cell proliferation and migration via EdU incorporation, CCK8 and transwell assays in vitro.
RESULTS
We found that FAM111B can enhance oncogenesis and progression in multiple tumor types. The clinical cohort of GC showed that upregulation of FAM111B is associated with early recurrence of GC, and knockdown of the FAM111B gene can inhibit the proliferation and migration of GC cells. Gene enrichment analysis indicates that FAM111B promotes cancer through immune system process, chromosome instability, DNA repair, and apoptosis regulation. Mechanistically, FAM111B appears to promote the growth cycle of malignant tumor cells while inhibiting apoptosis.
CONCLUSION
FAM111B may serve as a potential pan-cancer biomarker for predicting the prognosis and survival of malignant tumor patients. Our study elucidates the role of FAM111B in the occurrence and development of various cancers, and highlights the need for future research on FAM111B in cancers.
PubMed: 37213474
DOI: 10.2147/IJGM.S409690 -
EMBO Reports Oct 2020Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome, yet how FAM111A mutations...
Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome, yet how FAM111A mutations lead to disease is not known. We show that FAM111A proteolytic activity suppresses DNA replication and transcription by displacing key effectors of these processes from chromatin, triggering rapid programmed cell death by Caspase-dependent apoptosis to potently undermine cell viability. Patient-associated point mutations in FAM111A exacerbate these phenotypes by hyperactivating its intrinsic protease activity. Moreover, FAM111A forms a complex with the uncharacterized homologous serine protease FAM111B, point mutations in which cause a hereditary fibrosing poikiloderma syndrome, and we demonstrate that disease-associated FAM111B mutants display amplified proteolytic activity and phenocopy the cellular impact of deregulated FAM111A catalytic activity. Thus, patient-associated FAM111A and FAM111B mutations may drive multisystem disorders via a common gain-of-function mechanism that relieves inhibitory constraints on their protease activities to powerfully undermine cellular fitness.
Topics: Bone Diseases, Developmental; Cell Cycle Proteins; Gain of Function Mutation; Humans; Hyperostosis, Cortical, Congenital; Mutation; Peptide Hydrolases; Receptors, Virus
PubMed: 32776417
DOI: 10.15252/embr.202050662 -
Cureus Apr 2024Kindler syndrome (KS) is a rare autosomal recessive skin condition. The FERMT1 gene mutates and causes symptoms such as blistering and epidermal atrophy, as well as an...
Kindler syndrome (KS) is a rare autosomal recessive skin condition. The FERMT1 gene mutates and causes symptoms such as blistering and epidermal atrophy, as well as an increased risk of cancer and poor wound healing. A male in his 20s sought treatment for his hyper-hypopigmentation over the body with poikiloderma of the face with thin wrinkled cigarette paper skin in association with photosensitivity. He gave a history of developing blisters all over the body during his childhood, which formed raw areas and eventually healed forming atrophic scars. The objective is to assess the correlation of clinical findings with dermoscopy in a case of KS. KS is a rare disorder with poikiloderma, photosensitivity, and acral bullae in infancy as predominant features. Dermoscopy proves to be a useful tool in the diagnosis of this rare disorder as it helps in the identification of poikiloderma, adermatoglyphia, and cigarette paper scarring.
PubMed: 38765347
DOI: 10.7759/cureus.58433