A novel mutation in the proteolytic domain of LONP1 causes atypical CODAS syndrome

Inui, Tomoyuki; Anzai, Mai; Takezawa, Yusuke; Endo, Wakaba; Kakisaka, Yosuke; Kikuchi, Atsuo; Ônuma, Akira; Kure, Shigeo; Nishino, Ichizo; Ohba, Chihiro; Saitsu, Hirotomo; Matsumoto, Naomichi; Haginoya, Kazuhiro

doi:10.1038/jhg.2017.11

Cited by 19 publications

(25 citation statements)

References 12 publications

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“…Conversely, het mice appear healthy, and we did not detect any gross phenotypic, nor histological alterations which could suggest the presence of inflammatory status or functional alterations of muscles, bones, nervous system and digestive tract. This is in agreement with previous studies performed on another Lonp wt/− mouse model [32,42] and with that observed in the parents of CODAS-affected patients, who appear healthy and without relevant phenotypic alterations, despite the mutation in one copy of LONP1 [36,39,45].…”

Section: Discussionsupporting

confidence: 93%

Impaired Mitochondrial Morphology and Functionality in Lonp1wt/− Mice

Gaetano

Gibellini

Bianchini

et al. 2020

JCM

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LONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of LONP1 have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which Lonp1 was ablated. The homozygous Lonp−/− mouse was not vital, while the heterozygous Lonp1wt/− showed similar growth rate, weight, length, life-span and histologic features as wild type. Conversely, ultrastructural analysis of heterozygous enterocytes evidenced profound morphological alterations of mitochondria, which appeared increased in number, swollen and larger, with a lower complexity. Embryonic fibroblasts (MEFs) from Lonp1wt/− mice showed a reduced expression of Lonp1 and Tfam, whose expression is regulated by LONP1. Mitochondrial DNA was also reduced, and mitochondria were swollen and larger, albeit at a lesser extent than enterocytes, with a perinuclear distribution. From the functional point of view, mitochondria from heterozygous MEF showed a lower oxygen consumption rate in basal conditions, either in the presence of glucose or galactose, and a reduced expression of mitochondrial complexes than wild type. In conclusion, the presence of one functional copy of the Lonp1 gene leads to impairment of mitochondrial ultrastructure and functions in vivo.

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Section: Discussionsupporting

confidence: 93%

Impaired Mitochondrial Morphology and Functionality in Lonp1wt/− Mice

Gaetano

Gibellini

Bianchini

et al. 2020

JCM

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“…To date, there are a few case reports of a LONP1 manifesting with a mitochondrial disease phenotype (5, 8). Other reports of recessively inherited variants in LONP1 have been described in relation to CODAS syndrome (6, 7, 9), which could be distinguished from classical mitochondrial diseases by its distinctive clinical anomalies. However, patients with CODAS manifest with a varying clinical spectrum that may mimic that of a classical mitochondrial disease, including but not limited to, short stature, ptosis, hypotonia, and intellectual disability (6, 7, 26).…”

Section: Discussionmentioning

confidence: 99%

“…In 2017, a group from Japan identified a compound heterozygous variant in LONP1 on whole exome sequencing in a 12-year-old male with atypical CODAS (9). His manifestations included severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia, motor regression, and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on MRI (9). Muscle biopsy was not performed; therefore, it is unclear if this case represented a LONP1 -related mitochondrial cytopathy.…”

Section: Introductionmentioning

confidence: 99%

Expanding the Clinical Spectrum of LONP1-Related Mitochondrial Cytopathy

et al. 2019

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Pathogenic variants in the LONP1 gene have been associated with CODAS syndrome (Cerebral, Ocular, Dental, Auricular, and Skeletal Anomalies Syndrome). A recent report identified the first newborn case with LONP1-related mitochondrial cytopathy due to a compound heterozygous pathogenic variant in LONP1 without features of CODAS. The proband had manifested with severe congenital lactic acidosis and profound multiple respiratory chain complex activity deficiencies associated with the quantitative loss of mtDNA copy number in muscle. A subsequent report identified two siblings with regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability, progressive cerebellar atrophy, where muscle biopsy showed an electron dense mitochondrial inclusions without ragged-red fibers and normal electron transport chain enzyme activities. Here, we report an additional case of autosomal recessive mitochondrial cytopathy due to a homozygous missense variant in LONP1 that was identified on whole exome sequencing (c.810G > A; p.D463N). The proband, a 20-year-old male born to consanguineous parents, presented with global developmental delay, emotional outbursts, speech and swallowing difficulties, hypotonia, and ataxia since childhood. Muscle biopsy showed massive granular bodies, increased oxidative stress, and autophagic block and reduced mitochondrial state 3 respiration. We have identified another case of LONP1-related mitochondrial cytopathy further confirming a neurological phenotype without CODAS features.

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“…However, there are skeletal and dental anomalies that are pathognomonic for CODAS syndrome. Recently, one individual presenting atypical CODAS syndrome with myopathy resembling Marinesco–Sjögren syndrome was described ( 20 ). Furthermore, a c.2014C > T, p.(Arg627Cys) LONP1 variant has also been implicated in causing both CODAS syndrome and isolated paediatric cataracts ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease

Peter

Waddington

Oláhová

et al. 2018

Human Molecular Genetics

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LonP1 is a mitochondrial matrix protease whose selective substrate specificity is essential for maintaining mitochondrial homeostasis. Recessively inherited, pathogenic defects in LonP1 have been previously reported to underlie cerebral, ocular, dental, auricular and skeletal anomalies (CODAS) syndrome, a complex multisystemic and developmental disorder. Intriguingly, although classical mitochondrial disease presentations are well-known to exhibit marked clinical heterogeneity, the skeletal and dental features associated with CODAS syndrome are pathognomonic. We have applied whole exome sequencing to a patient with congenital lactic acidosis, muscle weakness, profound deficiencies in mitochondrial oxidative phosphorylation associated with loss of mtDNA copy number and MRI abnormalities consistent with Leigh syndrome, identifying biallelic variants in the LONP1 (NM_004793.3) gene; c.1693T > C predicting p.(Tyr565His) and c.2197G > A predicting p.(Glu733Lys); no evidence of the classical skeletal or dental defects observed in CODAS syndrome patients were noted in our patient. In vitro experiments confirmed the p.(Tyr565His) LonP1 mutant alone could not bind or degrade a substrate, consistent with the predicted function of Tyr565, whilst a second missense [p.(Glu733Lys)] variant had minimal effect. Mixtures of p.(Tyr565His) mutant and wild-type LonP1 retained partial protease activity but this was severely depleted when the p.(Tyr565His) mutant was mixed with the p.(Glu733Lys) mutant, data consistent with the compound heterozygosity detected in our patient. In summary, we conclude that pathogenic LONP1 variants can lead to a classical mitochondrial disease presentations associated with severe biochemical defects in oxidative phosphorylation in clinically relevant tissues.

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A novel mutation in the proteolytic domain of LONP1 causes atypical CODAS syndrome

Cited by 19 publications

References 12 publications

Impaired Mitochondrial Morphology and Functionality in Lonp1wt/− Mice

Impaired Mitochondrial Morphology and Functionality in Lonp1wt/− Mice

Expanding the Clinical Spectrum of LONP1-Related Mitochondrial Cytopathy

Defective mitochondrial protease LonP1 can cause classical mitochondrial disease

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