Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1

Ott, Claus‐Eric; Fischer, Björn; Schröter, Phillipe; Richter, Reyk; Gupta, Neerja; Verma, Nishant; Kabra, Madhulika; Mundlos, Stefan; Rajab, Anna; Neitzel, Heidemarie; Kornak, Uwe

doi:10.1016/j.bone.2013.04.007

Cited by 23 publications

(26 citation statements)

References 35 publications

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“…In individuals who carry the FUT2 p.Trp154* variant, there is lower expression of OSTM1 (MIM: 607649). In humans, OSTM1 mutations cause autosomal-recessive, rare, severe osteopetrosis (MIM: 259720), a condition characterized by reduced osteoclast number and activity, bony sclerosis, fractures, reduced bone marrow cavities, pancytopenia, recurrent infections, and early death, 40 consistent with hematopoietic and osteoclast defects in gl/Ostm1-mutant mice. 41 Since we identified individuals with FUT2 stop variants with cholesteatomas and/or downregulated OSTM1 expression, reduced FUT2 levels might play a role in cholesteatoma formation and bone pathology in part via decreased OSTM1 levels.…”

Section: Discussionmentioning

confidence: 99%

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Santos‐Cortez

Chiong

Frank

et al. 2018

The American Journal of Human Genetics

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Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154*) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202*) variant co-segregates with otitis media in a Filipino pedigree (LOD ¼ 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p ¼ 1.2 3 10 À5) and US trios (TDT p ¼ 0.01). The c.461G>A (p.Trp154*) variant was also overtransmitted in US trios (TDT p ¼ 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10 À7) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p ¼ 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154*, and p.Arg202*-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.

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Section: Discussionmentioning

confidence: 99%

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Santos‐Cortez

Chiong

Frank

et al. 2018

The American Journal of Human Genetics

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“…Children with malignant infantile osteopetrosis (MIOP), the lethal form of OP, exhibit an array of symptoms including pancytopenia, defective bone metabolism, and neurologic abnormalities such as progressive blindness, seizures, and eventual death if untreated; symptoms are secondary to both bony overgrowth and direct neurotoxicity. [1][2][3][4][5][6][7] To date, mutations in 12 genes have been associated with the OP phenotype, most commonly in the TCIRG1 (50%), CLCN7 (15%), 8,9 and OSTM1 (5%) genes. 2,3 Although the average lifespan for a patient with MIOP is 5 to 6 years of age, patients specifically with OSTM1 mutations display a more severe, intrinsic neurodegenerative process, and death generally occurs earlier, between 0 and 2 years of age.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic cell transplantation for a child with OSTM1 osteopetrosis

et al. 2016

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“…The neuronal complications have been secondarily ascribed to abnormal bone accumulation in osteopetrosis that compresses cranial nerves, resulting in optic atrophy and blindness as well as hearing impairment (2). However, there is recent evidence for primary central nervous system (CNS) defects in osteopetrotic patients with OSTM1 and ClC7 mutations (3)(4)(5)(6)(7). Of interest, OSTM1 mutations lead to both more severe osteopetrosis and CNS defects (8,9).…”

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confidence: 99%

Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency

Héraud

Griffiths

Pandruvada

et al. 2014

Journal of Biological Chemistry

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Background: Although loss of the Ostm1 gene leads to the most severe form of osteopetrosis, Ostm1 is expressed in other tissues, including the CNS. Results: Independently of hematopoietic lineages, loss of Ostm1 results in acute neurodegeneration with enhanced autophagy. Conclusion: We present evidence for an Ostm1 cell-autonomous role in neurons. Significance: This study shows a novel molecular pathogenic mechanism for neurodegeneration-related diseases.

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Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1

Cited by 23 publications

References 35 publications

FUT2 Variants Confer Susceptibility to Familial Otitis Media

FUT2 Variants Confer Susceptibility to Familial Otitis Media

Hematopoietic cell transplantation for a child with OSTM1 osteopetrosis

Severe Neurodegeneration with Impaired Autophagy Mechanism Triggered by Ostm1 Deficiency

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