Iron-sulfur protein NUBPL (IND1) also known as nucleotide-binding protein-like (NUBPL) is an iron-sulfur (Fe/S) protein that, in humans, is encoded by the NUBPLgene, located on chromosome 14q12. It that has an early role in the assembly of the mitochondrial complex I assembly pathway.
Discovery
Sheftel, et al. (2009) used RNA interference (RNAi) to delete the NUBPL gene in yeast (Y. lipolytica). They observed decreased levels and activity of mitochondrial complex I, leading them to conclude that NUBPL is required for complex I assembly and activity. Their experiments showed functional conservation of NUBPL in yeast and humans, an indication that the protein serves an important function. Sheftel, et al. observed structural abnormalities in mitochondria that were NUBPL-depleted mitochondria. These abnormalities included the loss of crista membranes, remodeling of the respiratory supercomplexes, and increased lactate production.[1]
Clinical significance
The absence of NUBPL disrupts the early stage of the mitochondrial complex I assembly pathway. NUBPL-depleted cells were observed to have an abnormal sub complex of proteins normally found in the membrane arm of complex I. A decrease in the presence of complex I subunit proteins, NDUFS1, NDUFV1, NDUFS3, and NDUFA13, indicated a failure of normal complex I assembly.[1]
High-throughput DNA sequencing was used to identify variants in 103 candidate genes in 103 patients with mitochondrial complex 1 disorders. Heterozygous variants in the NUBPL were identified in one patient. cDNA complementation studies showed that the variants can cause complex 1 deficiency. The finding in this patient is consistent with autosomal recessive inheritance NUBPL-associated complex I deficiency, and supports the pathogenicity of the variants that were identified.[2] Complex compound heterozygous variants were identified in the NUBPL gene in this patient.[2] In exon 2, a paternally-inherited G->A point mutation (c.166 G>A) resulting in missense substitution of gly56-to-arg (G56R) was observed. Two variants were maternally-inherited: T->C point mutation (c.815-27 T>C) that caused a splicing error and a complex deletion of exons 1-4 and duplication involving exon 7. Two of 232 (1%) control chromosomes were found to have the c.166 G>A pathogenic variant. This individual identified was noted to have motor delays and developmental delay at 2 years of age.[2] He never achieved independent walking. He developed myopathy, nystagmus, ataxia, upper motor neuron signs, and absence seizures. Brain MRI showed leukodystrophy with involvement of the cerebellar cortex and deep white matter. At age 8, he had spasticity, ataxia, and speech problems.
Several patients from with early MRI abnormalities of the cerebellum, deep cerebral white matter and corpus callosum. In this small sample, it was noted that later imaging studies showed improvements to the corpus callosum and cerebral white matter abnormalities, while the cerebellar abnormalities worsen and brainstem abnormalities arise. Using whole exome sequencing, four of the patientshad a mitochondrial complex І deficiency identified using other laboratory methods. All four of the patients had compound pathogenic variants in the NUBPL gene.[3]
