Background
Methods
Research subjects
Genome-wide SNP genotyping and homozygosity mapping
High-throughput sequencing of nuclear and mitochondrial DNA
Transcript analysis
Sanger DNA sequencing
Fibroblast culturing
Quantitative PCR (QPCR) of mt-RNAs of ND1, ND2 and ATP8 genes
Western blots
Results
The five affected children in the studied family exhibited global developmental delay
Genome-wide genotyping of the two branches in the studied family mapped the disease to a single locus on chromosome 17
Next-generation sequencing revealed a splicing aberration in the nuclear gene ELAC2 while their mtDNA was normal
The c.1423+2T>A mutation in ELAC2 altered its mRNA splicing pattern and reduced its protein expression
The 5′ end unprocessed mt-RNAs in patient’s fibroblasts are significantly elevated
Discussion
Families | F1 | F2 | F3 | F316 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Ethnic | German | Arabic | Turkish | Pakistani | ||||||
Patients | #61525 (II-2) | #57415 (II-3) | #61982 (II-5) | #36355 (II-1) | #36355 (II-2) | V-2 | V-4 | V-5 | V-10a
| V-11 |
Sex | M | M | F | F | F | F | M | F | M | F |
Clinical features | ||||||||||
Microcephaly | + | + | ? | ? | ? | ? | ? | ? | + | + |
Psychomotor retardation | + | + | ? | ? | ? | + | + | + | + | + |
Muscle hypotonia | - | + | + | - | + | ? | ? | ? | + | + |
HCM | + | + | + | + | + later DCM | ? | ? | ? | Mild septal Hypertrophy | Mild septal Hypertrophy |
Brain MRI | NA | Hyper-intensities in basal ganglia | NA | NA | Normal at 20 months | NA | NA | NA | Reduced volume of cerebellar vermis + hemispheres | NA |
Lactic acid level in blood | Increased | Increased | Increased | Increased | ? | NA | NA | NA | Slightly increased | NA |
Mitoch. function in muscle | NA | Decreased complex I | Decreased complex I | Decreased complex I, IV | Decreased complex I, IV | NA | NA | NA | NA | NA |
Course | death at 6 months | Alive at 2.10 years | death at 11 months | alive at 13 years | death at 4.9 years | alive at 19 years | alive at 17 years | alive at 15 years | alive at 4 years | alive at 2.5 years |
mtDNA | normal | NA | NA | NA | NA | NA | NA | NA | normal | NA |
Zygosity | Compound Heterozygous | Homozygous | Homozygous | Homozygous | ||||||
DNA change | c.[631C > T; 1559C > T] | c.460 T > C | c.1267C > T | c.1423 + 2 T > A | ||||||
Protein change | p.[Arg211a; Thr520Ile] | p.Phe154Leu | p.Leu423Phe | frameshift | ||||||
References | Haack et al. 2013 [3] | This study |