Pedigrees of family A and family B with autosomal recessive achromatopsia originating from the United Arab Emirates and carrying mutations in the CNGA3 gene

Family A has two branches carrying either the two heterozygous mutations R283W and G397V or being homozygous for the mutation G397V due to consanguinity of the parents. Patients of family B are both homozygous for the mutation R283W in the CNGA3 gene. Squares indicate males and circles females. Open symbols indicate healthy individuals, while shadings designate the affected patients. Arrows point to family members for whom DNA samples were available for genetic analysis. CNGA3 genotypes are given below each analyzed individual.<p><b>Copyright information:</b></p><p>Taken from " mutations in two United Arab Emirates families with achromatopsia"</p><p></p><p>Molecular Vision 2008;14():1293-1297.</p><p>Published online 10 Jul 2008</p><p>PMCID:PMC2464613.</p><p></p

Ophthalmological findings in 74 patients with mitochondrial disease

<p><i>Background</i>: Mitochondrial disease often manifests with ophthalmologic signs and symptoms. Due to the important role of mitochondria in aerobic metabolism, the eyes are among the more preferentially involved organs. The clinical diagnosis of mitochondrial disease can be facilitated by an improved knowledge of the types and magnitude of their various manifestations. The aim of this study was to describe the ophthalmological manifestations of patients with mitochondrial diseases that are currently not well elucidated.</p> <p><i>Methods</i>: From a database of patients with verified primary mitochondrial disease (<i>n</i> = 81) who had visited our institution we identified 74 patients who had ophthalmologic examinations. Demographic, clinical, and ophthalmologic data were collected. Institutional review board approval was obtained.</p> <p><i>Results</i>: A total of 74 patients were identified with Leigh disease, MELAS, MERRF, CPEO, Pearson/Kearns-Sayre syndrome, as well as other mtDNA point mutations, deletions, depletions, and mutations. Overall, 26 of the 74 patients (35%) had one or more ophthalmological abnormalities. Retinal pigmentary changes were present in 12/74 (16%) of patients. Partial or total optic atrophy (OA) was noted in 8/74 (10%) of patients. Decreased extra-ocular movement (EOM) was noted in 6/74 (8%) of patients. Other ophthalmological findings included macular atrophy (2/74), macular dystrophy (1/74), and visual field defects (1/74).</p> <p><i>Conclusions</i>: Over one-third of our cohort of patients with mitochondrial disorders had ophthalmological manifestations, some of which affected vision significantly. Eye examinations are critical in patients with mitochondrial disease so that complete assessments of the effects of the underlying mutations are uncovered and the appropriate counseling and care are given.</p

Identification of regulatory deletions telomeric to <i>PAX6</i>.

<p>Regulatory deletions telomeric to <i>PAX6</i> were identified in individual 1514 (chr11:30,874,642–31,654,833), individual 753 (chr11:30,967,000–31,704,000), individual 555 (chr11:31,108,579–31,649–842), individual 2014 (chr11:31,234,395–31,751,815) and individual 659 (chr11:31,379,000–31,708,000). The schematic diagram shows how the ‘critical region’ (delimited by grey dotted lines) required for <i>PAX6</i> transcriptional activation was delineated by combining our data with published deletions with known coordinates [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref055" target="_blank">55</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref067" target="_blank">67</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref068" target="_blank">68</a>]. <i>PAX6</i> regulatory deletions from the present study are shown by red blocks. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18.</p

Details of the clinical diagnoses and genetic pathology identified in individuals in this study.

<p>Details of the clinical diagnoses and genetic pathology identified in individuals in this study.</p

Identification of a potential <i>PITX2</i> regulatory deletion.

<p>Genome-wide array CGH identified a deletion of approximately 3.5 Mb in individual 1194 (chr4:111,994,000–115,504,000) (red bar). The deletion is located telomeric to the <i>PITX2</i> gene on chromosome 4. The positions of conserved elements (CE) in the deleted region, as identified by Volkmann et al., 2011 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153757#pone.0153757.ref047" target="_blank">47</a>] are marked by orange ellipses. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are shown on the x-axis and are based on the Human Genome Assembly hg18.</p

Mutation analysis of the <i>FOXC1</i> locus.

<p><b>(A)</b> Genome-wide array CGH identified two deletions encompassing the <i>FOXC1</i> gene in individuals 1449 (chr6:1,543,591–1,675,085) and 1246 (chr6:1,543,591–1,675,085). <b>(B)</b> Direct sequencing of the <i>FOXC1</i> coding region identified a heterozygous substitution in individual 1839 (c.235C>A, p.(Pro79Thr)) and another in individual 1634 (c.302T>C, p.(Leu101Pro)). <i>FOXC1</i> mutation screening in unaffected parents of both patients showed that the mutations had occurred <i>de novo</i>. The locations of both mutations within the fork-head domain of the FOXC1 protein are indicated by vertical arrows. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18. The genomic sequence identifier for <i>FOXC1</i> is NG_009368.</p

Identification of <i>PAX6</i> whole-gene deletions.

<p>Genome-wide array CGH analysis identified a 650 kb deletion in individual 2193 (chr11:31,199,000–31,849,000), a 520 kb deletion in individual 377 (chr11:31,394,000–31,914,000), a 154 kb deletion in individual 1510 (chr11:31,779,000–31,933,000) and a 96 kb deletion in individual 1977 (chr11:31,698,271–31,794,414), all involving <i>PAX6</i>. Red bars show the position of the deletions. Genes transcribed on the forward strand are in blue and those transcribed on the reverse strand are in green, also indicated by arrows. Genomic coordinates are based on the Human Genome Assembly hg18.</p