Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in <scp><i>MBTPS1</i></scp>

Carvalho, Daniel R.; Speck‐Martins, Carlos E.; Brum, Jaime Moritz; Ferreira, Carlos R.; Sobreira, Nara

doi:10.1002/ajmg.a.61614

Cited by 15 publications

(13 citation statements)

References 9 publications

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“…Previous studies have shown that S1P is essential for lysosomal biogenesis (Carvalho et al , 2020), and abnormal lysosomes were consistently found in patients (Fig EV2A, lower panel). Lipid deposition was observed in the patient’s skin lesions, as evidenced by increased cytoplasmic lipid droplets (Fig EV2A, lower panel).…”

Section: Resultssupporting

confidence: 51%

“…A significant increase in the number of mitochondria (161.5% increase) and morphological abnormalities in the mitochondria (100.7% increase in the length and 10.3% decrease in the length-towidth ratio) were observed in the skin lesions of patient 1 by Previous studies have shown that S1P is essential for lysosomal biogenesis (Carvalho et al, 2020), and abnormal lysosomes were consistently found in patients (Fig EV2A,lower panel). Lipid deposition was observed in the patient's skin lesions, as evidenced by increased cytoplasmic lipid droplets (Fig EV2A,lower panel).…”

Section: S1p Deficiency Causes Abnormal Mitochondrial Morphology and ...mentioning

confidence: 69%

“…Rare cases with neurocognitive delays, three cases with disordered skeletal development, and muscle lesions in another patient have been reported with MBTPS1 variants (Kondo et al , 2018; Schweitzer et al , 2019; Carvalho et al , 2020; Meyer et al , 2020). Our study further indicated that MBTPS1 variants cause CAOP syndrome.…”

Section: Discussionmentioning

confidence: 99%

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S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome

Chen

Wang

et al. 2022

EMBO Mol Med

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In this report, we discovered a new entity named cataract, alopecia, oral mucosal disorder, and psoriasis‐like (CAOP) syndrome in two unrelated and ethnically diverse patients. Furthermore, patient 1 failed to respond to regular treatment. We found that CAOP syndrome was caused by an autosomal recessive defect in the mitochondrial membrane‐bound transcription factor peptidase/site‐1 protease (MBTPS1, S1P). Mitochondrial abnormalities were observed in patient 1 with CAOP syndrome. Furthermore, we found that S1P is a novel mitochondrial protein that forms a trimeric complex with ETFA/ETFB. S1P enhances ETFA/ETFB flavination and maintains its stability. Patient S1P variants destabilize ETFA/ETFB, impair mitochondrial respiration, decrease fatty acid β‐oxidation activity, and shift mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis. Mitochondrial dysfunction and inflammatory lesions in patient 1 were significantly ameliorated by riboflavin supplementation, which restored the stability of ETFA/ETFB. Our study discovered that mutations in MBTPS1 resulted in a new entity of CAOP syndrome and elucidated the mechanism of the mutations in the new disease.

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Section: Resultssupporting

confidence: 51%

Section: S1p Deficiency Causes Abnormal Mitochondrial Morphology and ...mentioning

confidence: 69%

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S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome

Chen

Wang

et al. 2022

EMBO Mol Med

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“…A phenotype substantially different from the case has been reported by Kondo et al [ 3 ] and our proband. Another case of Kondo-Fu type spondyloepiphyseal dysplasia (SEDKF) was reported with unique findings in a 5-year-old Brazilian girl with epilepsy and craniosynostosis [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a New Variant of the MBTPS1 Gene of the Kondo-Fu Type of Spondyloepiphyseal Dysplasia (SEDKF) in a Saudi Patient

Alotaibi

Aldossari

Khan

et al. 2022

Case Reports in Pediatrics

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Spondyloepiphyseal dysplasia (SEDKF) is a rare skeletal dysplasia associated with kyphosis and low bone mineral density, significantly delayed growth, and skeletal deformities. Blood lysosomal enzyme levels have also been shown to be elevated with a delay in development. The first variant described was compound heterozygosity for mutations in the MBTPS1 gene: a 1-bp duplication and a missense mutation. In the current study, we examined a Saudi consanguineous family. Clinical features like spondyloepiphyseal dysplasia, indicative of characteristic skeletal abnormalities, and impaired cognitive abilities were observed. Our patient has dysmorphic facial features, short stature, and significant skeletal deformities. A homozygous missense MBTPS1 (c.2634C > A p. (Ser878Arg)) with unknown significance was discovered in the whole exome; pathogenic MBTPS1 variants cause the autosomal recessive Kondo-Fu type of spondyloepiphyseal dysplasia (SEDKF, OMIM®: 618392). The whole exome sequence, which described a homozygous missense variant of unknown clinical significance (VUS, class 3 variant) in the MBTPS1 gene, was heterozygous in both asymptomatic parents. We are mindful that changing the classification of a variant of unknown significance is challenging. Considering clinical phenotypes and radiological findings produced by the pathogenic mutation in the MBTPS1 gene, the identified c.2634C > A variant is supported and may be categorized as likely pathogenic based on clinical symptoms.

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“…To date, only three patients have been reported to carry the MBTPS1 variants. The affected individuals had similar clinical manifestations, presenting severely growth retardation, dysmorphic facial features including large ears, prominent forehead and cheekbones, skeletal dysplasia and cataract ( 1 – 3 ). Besides, epilepsy, craniosynostosis and hernia were reported in different individuals.…”

Section: Introductionmentioning

confidence: 99%

Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant

Yuan

Zhou²,

Wang³

et al. 2023

Front. Pediatr.

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BackgroundA novel autosomal recessive skeletal dysplasia resulting from pathogenic variants in membrane-bound transcription factor peptidase, site 1 (MBTPS1) has been recently delineated. To date, only three patients have been reported.MethodsIn this study, we reported the clinical and molecular features of a Chinese boy who was diagnosed with spondyloepiphyseal dysplasia. The effects of variants on mRNA splicing were analyzed through transcript analysis in vivo and minigene splice assay in vitro.ResultsThe proband mainly showed short stature, special facial features, cataract, hernias, and serious sleep apnea syndrome. Growth hormone stimulation tests suggested the boy had growth hormone deficiency. Imaging examinations suggested abnormal thoracolumbar vertebrae and severely decreased bone mineral density. Genetic analysis of MBTPS1 gene revealed two novel heterozygous variants, a nonsense mutation c.2656C > T (p.Q886*, 167) in exon 20 and a synonymous variant c.774C > T (p.A258=) in exon 6. The transcript analysis in vivo exhibited that the synonymous variant c.774C > T caused exon 6 skipping. The minigene splice assay in vitro confirmed the alteration of MBTPS1 mRNA splicing and the exon skipping was partially restored by an antisense oligonucleotide (ASO) treatment.ConclusionNotably, we report a Chinese rare case of spondyloepiphyseal dysplasia and validate its pathogenic synonymous variant in the MBTPS1 gene.

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Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in MBTPS1

Cited by 15 publications

References 9 publications

S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome

S1P defects cause a new entity of cataract, alopecia, oral mucosal disorder, and psoriasis‐like syndrome

Identification of a New Variant of the MBTPS1 Gene of the Kondo-Fu Type of Spondyloepiphyseal Dysplasia (SEDKF) in a Saudi Patient

Clinical and molecular characterization of a patient with MBTPS1 related spondyloepiphyseal dysplasia: Evidence of pathogenicity for a synonymous variant

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