A second family with autosomal recessive spondylometaphyseal dysplasia and early death

Mégarbané, André; Mehawej, Cybel; Zahr, Amir El; Haddad, Samuel; Cormier‐Daire, Valérie

doi:10.1002/ajmg.a.36372

Cited by 7 publications

(11 citation statements)

References 10 publications

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“…Homozygous missense mutations in Magmas (N76D and Q74P) results in Spondylometaphyseal dysplasia, Megarbane-Dagher-Melki type (SMDMDM) ( Table 1) [ [85][86][87][88]. SMDMDM is a rare autosomal recessive disorder characterised by skeletal abnormalities, severe chondrodysplasia, dysmorphic facial appearance, growth retardation, developmental delay and early death [85][86][87][88]. The skeletal dysplasia seen in SMDMDM is uncommon in mitochondrial disorders, however Magmas expression detected in the distal femurs of mice suggests a role for this protein in skeletogenesis [87].…”

Section: Magmas and Spondylometaphyseal Dysplasia Megarbane-dagher-mmentioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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The majority of proteins localised to mitochondria are encoded by the nuclear genome, with approximately 1500 proteins imported into mammalian mitochondria. Dysfunction in this fundamental cellular process is linked to a variety of pathologies including neuropathies, cardiovascular disorders, myopathies, neurodegenerative diseases and cancer, demonstrating the importance of mitochondrial protein import machinery for cellular function. Correct import of proteins into mitochondria requires the co‐ordinated activity of multimeric protein translocation and sorting machineries located in both the outer and inner mitochondrial membranes, directing the imported proteins to the destined mitochondrial compartment. This dynamic process maintains cellular homeostasis, and its dysregulation significantly affects cellular signalling pathways and metabolism. This review summarises current knowledge of the mammalian mitochondrial import machinery and the pathological consequences of mutation of its components. In addition, we will discuss the role of mitochondrial import in cancer, and our current understanding of the role of mitochondrial import in neurodegenerative diseases including Alzheimer's disease, Huntington's disease and Parkinson's disease.

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Section: Magmas and Spondylometaphyseal Dysplasia Megarbane-dagher-mmentioning

confidence: 99%

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

2021

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“…Here, we report the identification of a homozygous missense MAGMAS mutation, (p.Asn76Asp), in patients from two unrelated Lebanese families, affected with a rare lethal spondylometaphyseal dysplasia recently described by Mégarbané et al [6], [7]. By reconstructing haplotypes from exome and STR genotyping data from patients F1-IV.3 and F2-IV.3, we were able to identify a minimal common ancestral homozygous haplotype around MAGMAS , spanning 1.9 Mb on chromosome 16p13.3, suggesting the existence of a founder mutation in gene.…”

Section: Discussionmentioning

confidence: 83%

“…Although different entities within the group of spondylodysplastic dysplasia are well defined, a few cases remain unclassified. Recently, Mégarbané et al have reported on two unrelated consanguineous Lebanese families with four affected cases presenting a novel type of early lethal spondylometaphyseal dysplasia [6] , [7] . To elucidate the molecular basis of this entity, we performed exome sequencing in these two distinct families and identified a homozygous mutation in MAGMAS (Mitochondria-associated granulocyte macrophage colony stimulating factor-signaling molecule) in patients from both families.…”

Section: Introductionmentioning

confidence: 99%

The Impairment of MAGMAS Function in Human Is Responsible for a Severe Skeletal Dysplasia

et al. 2014

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Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex process. Here, we report a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene (MAGMAS) in a novel and severe spondylodysplastic dysplasia. MAGMAS, also referred to as PAM16 (presequence translocase-associated motor 16), is a mitochondria-associated protein involved in preprotein translocation into the matrix. We show that MAGMAS is specifically expressed in trabecular bone and cartilage at early developmental stages and that the mutation leads to an instability of the protein. We further demonstrate that the mutation described here confers to yeast strains a temperature-sensitive phenotype, impairs the import of mitochondrial matrix pre-proteins and induces cell death. The finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia supports a key role for this mitochondrial protein in the ossification process.

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“…Wormian bones can be idiopathic, present as a minor skeletal variant or can occur with numerous recognized syndromes (Gorlin et al, 2001). Wormian bones are often found in osteogenesis imperfectas (Cremin et al, 1982; Semler et al, 2010), cleidocranial dysplasia (Mundlos, 1999) as well as other bone dysplasias (Langer et al, 1991; Horovitz et al, 1995; Santolaya et al, 1998; Garavelli et al, 2009; Megarbane et al, 2014; Palav et al, 2014). The occurrence of wormian bones is thought to be the result of disturbed osteogenesis/ossification or as a response to mechanical forces affecting sutures (Sanchez-Lara et al, 2007; Bellary et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Interfrontal Bone Among Inbred Strains of Mice and QTL Mapping

et al. 2019

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The interfrontal bone (IF) is a minor skeletal trait residing between the frontal bones. IF is considered a quasi-continuous trait. Genetic and environmental factors appear to play roles in its development. The mechanism(s) underlying IF bone development are poorly understood. We sought to survey inbred strains of mice for the prevalence of IF and to perform QTL mapping studies. Archived mouse skulls from a mouse phenome project (MPP) were available for this study. 27 inbred strains were investigated with 6–20 mice examined for each strain. Skulls were viewed dorsally and the IF measured using a zoom stereomicroscope equipped with a calibrated reticle. A two generation cross between C3H/HeJ and C57BL/6J mice was performed to generate a panel of 468 F2 mice. F2 mice were phenotyped for presence or absence of IF bone and among mice with the IF bone maximum widths and lengths were measured. F2 mice were genotyped for 573 SNP markers informative between the two strains and subjected to linkage map construction and interval QTL mapping. Results: Strain dependent differences in the prevalence of IF bones were observed. Overall, 77.8% or 21/27, of the inbred strains examined had IF bones. Six strains (C3H/HeJ, MOLF/EiJ, NZW/LacJ, SPRET/EiJ, SWR/J, and WSB/EiJ) lack IF bones. Among the strains with IF bones, the prevalence ranged from 100% for C57BL/6J, C57/LJ, CBA/J, and NZB/B1NJ and down to 5% for strains such as CAST/Ei. QTL mapping for IF bone length and widths identifies for each trait one strong QTL detected on chromosome 14 along with several other significant QTLs on chromosomes 3, 4, 7, and 11. Strain dependent differences in IF will facilitate investigation of genetic factors contributing to IF development. IF bone formation may be a model to understand intrasutural bone formation.

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A second family with autosomal recessive spondylometaphyseal dysplasia and early death

Cited by 7 publications

References 10 publications

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

Mitochondrial protein import dysfunction: mitochondrial disease, neurodegenerative disease and cancer

The Impairment of MAGMAS Function in Human Is Responsible for a Severe Skeletal Dysplasia

Interfrontal Bone Among Inbred Strains of Mice and QTL Mapping

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