TY - JOUR
T1 - A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families
AU - Aldosary, Mazhor
AU - Alsagob, Maysoon
AU - AlQudairy, Hanan
AU - González-Álvarez, Ana C.
AU - Arold, Stefan T.
AU - Dababo, Mohammad Anas
AU - Alharbi, Omar A.
AU - Almass, Rawan
AU - AlBakheet, AlBandary
AU - AlSarar, Dalia
AU - Qari, Alya
AU - Al-Ansari, Mysoon M
AU - Oláhová, Monika
AU - Al-Shahrani, Saif A.
AU - AlSayed, Moeenaldeen
AU - Colak, Dilek
AU - Taylor, Robert W.
AU - AlOwain, Mohammed
AU - Kaya, Namik
PY - 2022/10/7
Y1 - 2022/10/7
N2 - The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.
AB - The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in RTN4IP1, also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase. Here, we describe two unrelated consanguineous families from the northern region of Saudi Arabia harboring a missense variant (RTN4IP1:NM_032730.5; c.475G<T, p.Val159Phe) in the gene. Clinically affected individuals presented with intellectual disability, encephalopathy, ataxia, optic atrophy, and seizures. Based on whole exome sequencing and confirmatory Sanger sequencing, the variant was fully segregated with the phenotype in the families, absent among large ethnically matching controls as well as numerous in-house exomes, and predicted to be pathogenic by different in silico classifiers. Structural modeling and immunoblot analyses strongly indicated this variant to be pathogenic. Since the families belong to one of the tribal inhabitants of Saudi Arabia, we postulate that the variant is likely to be a founder. We provide the estimated age of the variant and present data confirming the disease-causality of this founder variant.
KW - Antioxidants
KW - Brain Diseases
KW - Carrier Proteins/genetics
KW - Humans
KW - Mitochondrial Proteins/genetics
KW - Mutation/genetics
KW - NADP/genetics
KW - Optic Atrophy/genetics
KW - Oxidoreductases/genetics
KW - Saudi Arabia
U2 - 10.3390/cells11193154
DO - 10.3390/cells11193154
M3 - Article
C2 - 36231115
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 19
M1 - 3154
ER -