Pseudotail as a feature of microphthalmia with linear skin defects syndrome

Alberry, Medhat; Juvanic, Gordan; Crolla, John A.; Soothill, Peter; Newbury‐Ecob, Ruth

doi:10.1097/mcd.0b013e328342eb66

Cited by 5 publications

(2 citation statements)

References 17 publications

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“…12,13 After this initial observation, heterozygous submicroscopic interstitial deletions and intragenic mutations of HCCS were detected in females with the classical MLS phenotype, confirming a pathogenic role for HCCS disruption in MLS. [1][2][3]7,14,15 More recently, heterozygous mutations in COX7B (MIM 300885; RefSeq NM_001866.2), located in chromosome band Xq21.1, have been found in girls who had linear skin defects as the predominant feature but who had no HCCS mutation or microphthalmia. 11 COX7B encodes a structural subunit of cytochrome c oxidase, also known as mitochondrial complex IV (cIV).…”

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confidence: 99%

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Rahden

Fernández-Vizarra

Alawi

et al. 2015

The American Journal of Human Genetics

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Microphthalmia with linear skin defects (MLS) syndrome is an X-linked male-lethal disorder also known as MIDAS (microphthalmia, dermal aplasia, and sclerocornea). Additional clinical features include neurological and cardiac abnormalities. MLS syndrome is genetically heterogeneous given that heterozygous mutations in HCCS or COX7B have been identified in MLS-affected females. Both genes encode proteins involved in the structure and function of complexes III and IV, which form the terminal segment of the mitochondrial respiratory chain (MRC). However, not all individuals with MLS syndrome carry a mutation in either HCCS or COX7B. The majority of MLS-affected females have severe skewing of X chromosome inactivation, suggesting that mutations in HCCS, COX7B, and other as-yet-unidentified X-linked gene(s) cause selective loss of cells in which the mutated X chromosome is active. By applying whole-exome sequencing and filtering for X-chromosomal variants, we identified a de novo nonsense mutation in NDUFB11 (Xp11.23) in one female individual and a heterozygous 1-bp deletion in a second individual, her asymptomatic mother, and an affected aborted fetus of the subject's mother. NDUFB11 encodes one of 30 poorly characterized supernumerary subunits of NADH:ubiquinone oxidoreductase, known as complex I (cI), the first and largest enzyme of the MRC. By shRNA-mediated NDUFB11 knockdown in HeLa cells, we demonstrate that NDUFB11 is essential for cI assembly and activity as well as cell growth and survival. These results demonstrate that X-linked genetic defects leading to the complete inactivation of complex I, III, or IV underlie MLS syndrome. Our data reveal an unexpected role of cI dysfunction in a developmental phenotype, further underscoring the existence of a group of mitochondrial diseases associated with neurocutaneous manifestations.

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Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Rahden

Fernández-Vizarra

Alawi

et al. 2015

The American Journal of Human Genetics

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“…The four deletions contain multiple genes including HCCS . Only three cryptic interstitial deletions covering HCCS have been reported in MLS-affected females so far: One of >3 Mb [13], a second of 3.6 Mb [38] and a third of 185–220 kb [30]. The two remaining MLS-affected females carried de novo intragenic sequence changes, the nonsense mutation c.589C > T (p.R197*) which seems to represent a recurrent mutation [4], and the novel mosaic 2-bp deletion c.[=/524_525delAG] (p.[=/E175Vfs*30])].…”

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confidence: 99%

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

Rahden

Rau

Fuchs

et al. 2014

Orphanet J Rare Dis

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BackgroundSegmental Xp22.2 monosomy or a heterozygous HCCS mutation is associated with the microphthalmia with linear skin defects (MLS) or MIDAS (microphthalmia, dermal aplasia, and sclerocornea) syndrome, an X-linked disorder with male lethality. HCCS encodes the holocytochrome c-type synthase involved in mitochondrial oxidative phosphorylation (OXPHOS) and programmed cell death.MethodsWe characterized the X-chromosomal abnormality encompassing HCCS or an intragenic mutation in this gene in six new female patients with an MLS phenotype by cytogenetic analysis, fluorescence in situ hybridization, sequencing, and quantitative real-time PCR. The X chromosome inactivation (XCI) pattern was determined and clinical data of the patients were reviewed.ResultsTwo terminal Xp deletions of ≥11.2 Mb, two submicroscopic copy number losses, one of ~850 kb and one of ≥3 Mb, all covering HCCS, 1 nonsense, and one mosaic 2-bp deletion in HCCS are reported. All females had a completely (>98:2) or slightly skewed (82:18) XCI pattern. The most consistent clinical features were microphthalmia/anophthalmia and sclerocornea/corneal opacity in all patients and congenital linear skin defects in 4/6. Additional manifestations included various ocular anomalies, cardiac defects, brain imaging abnormalities, microcephaly, postnatal growth retardation, and facial dysmorphism. However, no obvious clinical sign was observed in three female carriers who were relatives of one patient.ConclusionOur findings showed a wide phenotypic spectrum ranging from asymptomatic females with an HCCS mutation to patients with a neonatal lethal MLS form. Somatic mosaicism and the different ability of embryonic cells to cope with an OXPHOS defect and/or enhanced cell death upon HCCS deficiency likely underlie the great variability in phenotypes.

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Hereditary Disorders of the Dermis

Paller

Mancini

2016

Hurwitz Clinical Pediatric Dermatology

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Pseudotail as a feature of microphthalmia with linear skin defects syndrome

Cited by 5 publications

References 17 publications

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Mutations in NDUFB11, Encoding a Complex I Component of the Mitochondrial Respiratory Chain, Cause Microphthalmia with Linear Skin Defects Syndrome

Clinical spectrum of females with HCCS mutation: from no clinical signs to a neonatal lethal form of the microphthalmia with linear skin defects (MLS) syndrome

Hereditary Disorders of the Dermis

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