PT  - JOURNAL ARTICLE
AU  - Virginia Kimonis
AU  - Rehab al Dubaisi
AU  - Andrew E Maclean
AU  - Kathy Hall
AU  - Lan Weiss
AU  - Alexander E Stover
AU  - Philip H Schwartz
AU  - Bethany Berg
AU  - Cheng Cheng
AU  - Sumit Parikh
AU  - Blair R Conner
AU  - Sitao Wu
AU  - Anton N Hasso
AU  - Daryl A Scott
AU  - Mary Kay Koenig
AU  - Rachid Karam
AU  - Sha Tang
AU  - Moyra Smith
AU  - Elizabeth Chao
AU  - Janneke Balk
AU  - Eli Hatchwell
AU  - Peggy S Eis
TI  - <em>NUBPL</em> mitochondrial disease: new patients and review of the genetic and clinical spectrum
AID  - 10.1136/jmedgenet-2020-106846
DP  - 2021 May 01
TA  - Journal of Medical Genetics
PG  - 314--325
VI  - 58
IP  - 5
4099  - http://jmg.bmj.com/content/58/5/314.short
4100  - http://jmg.bmj.com/content/58/5/314.full
SO  - J Med Genet2021 May 01; 58
AB  - Background The nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).Methods Whole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts.Results The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3–18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.Conclusion We report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information.