NUBPL

Nucleotide-binding protein-like, also known as iron-sulfur protein required for NADH dehydrogenase or IND1, is an iron-sulfur (Fe/S) is_associated_with::protein that, in humans, is encoded by the NUBPL is_associated_with::gene, located on is_associated_with::chromosome 14q12. It that has an early role in the assembly of the mitochondrial complex I assembly pathway.

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.

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.

Clinical significance
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.

Complex compound heterozygous variants were identified in the NUBPL gene of the patient reported by Calvo, et al. (2010). 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.

The individual identified by Calvo et al. (2010) was noted to have motor delays and developmental delay at 2 years of age. 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.

Kevelam, et al (2013) identified 6 patients from 5 families with early MRI abnormalities of the cerebellum, deep cerebral white matter and corpus callosum. In their small sample, they 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. Four patients (2 were siblings) were tested with whole exome sequencing. All four of the patients who were tested had a mitochondrial complex І deficiency identified using other laboratory methods. All four of the patients had compound pathogenic variants in the NUBPL gene.

Support
Hope For Katherine is an active Facebook page and blog about Katherine Belle, a girl who has been diagnosed with mitochondrial disease due to NUBPL mutations. They want to connect with other families and health care providers who are treating patients NUBPL mutations. It is likely that complex I deficiency due to NUBPL mutations is underdiagnosed, although the growing use of whole exome sequencing for diagnosing rare disorders is expected to identify more patients with this mitochondrial disease subtype. As with many genetic disorders, we can gain a better understanding of NUBPL-associated complex I deficiency by studying and observing newly-diagnosed patients.

NUBPL.org was established in May 2015 to find other patients.