Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome

Abstract

Cerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored.

Mitochondrial Lon protease in human disease and aging: Including an etiologic classification of Lon-related diseases and disorders

“…Less than 20 cases have been reported to this day [65–67]. Two different groups reported in 2015 that the genetic abnormalities causing the CODAS Syndrome are compound heterozygous or homozygous mutations in LONP1 (either missense or nonsense point mutations or small in-frame deletions) [66,67]. The CODAS pattern of inheritance is autosomal recessive [66,67].…”

“…Two different groups reported in 2015 that the genetic abnormalities causing the CODAS Syndrome are compound heterozygous or homozygous mutations in LONP1 (either missense or nonsense point mutations or small in-frame deletions) [66,67]. The CODAS pattern of inheritance is autosomal recessive [66,67]. The amino acid substitutions cluster within the ATP-binding (AAA) and proteolytic domains of Lon [66,67].…”

“…The CODAS pattern of inheritance is autosomal recessive [66,67]. The amino acid substitutions cluster within the ATP-binding (AAA) and proteolytic domains of Lon [66,67]. Lymphoblastoid cell lines generated from CODAS patients have swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology, aggregated mt DNA-encoded subunit II of cytochrome c oxidase; and altered respiratory capacity, leading to impaired mitochondrial energy production [67].…”

Changes in specific protein degradation rates in Arabidopsis thaliana reveal multiple roles of Lon1 in mitochondrial protein homeostasis

“…Loss or interruption of Lon protease causes long-unviable filaments in bacteria (Donch and Greenberg, 1968), impaired ability to live on non-fermentable media in yeast (Suzuki et al, 1994;Van Dyck et al, 1994), delayed growth in plants (Rigas et al, 2009;Solheim et al, 2012), and caused CODAS syndrome in humans (Dikoglu et al, 2015;Strauss et al, 2015). Lon has two conserved protein domains: an AAA + domain for ATP-dependent protein binding related to a chaperone function and a p-domain with a S-K catalytic dyad that is responsible for proteolysis activity (Smith et al, 1999;Lee and Suzuki, 2008;Rigas et al, 2012).…”

Protein quality control at the interface of endoplasmic reticulum and mitochondria by Lon protease

“…() LonP1 was shown to be important for embryonic viability (Quiros et al ., ). In humans, pathological mutations in LonP1 are associated with CODAS (cerebral, ocular, dental, auricular and skeletal anomalies), a severe developmental disorder, the first‐ever human disease to be linked to LonP1 (Dikoglu et al ., ; Strauss et al ., ; Inui et al ., ). We believe that LonP1 is crucial for maintaining mitochondrial function not only during developmental stress but also during various pathological stresses that affect mitochondrial proteostasis.…”