Microphthalmia with Linear Skin Defects: A Case Report and Review

Sharma, Vishakha M.; Luzuriaga, Arlene Ruiz de; Waggoner, Darrel; Greenwald, Mark J.; Stein, Sarah L.

doi:10.1111/j.1525-1470.2008.00724.x

Cited by 25 publications

(22 citation statements)

References 25 publications

(77 reference statements)

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“…MLS is an X-linked dominant, male lethal phenotype characterized by microphthalmia or other ocular features, including corneal opacities in approximately 35 % and lesions of the skin that heal with age. MLS has also been associated with other variable systemic defects including short stature, congenital heart disease, central nervous system defects including developmental delay, genitourinary anomalies and hearing defects (Sharma et al 2008). The HCCS gene has 7 exons with exons 2–7 encoding for the protein holocytochrome c synthase (HCCS).…”

Section: Resultsmentioning

confidence: 99%

Whole exome sequence analysis of Peters anomaly

et al. 2014

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Peters anomaly is a rare form of anterior segment ocular dysgenesis, which can also be associated with additional systemic defects. At this time, the majority of cases of Peters anomaly lack a genetic diagnosis. We performed whole exome sequencing of 27 patients with syndromic or isolated Peters anomaly to search for pathogenic mutations in currently known ocular genes. Among the eight previously recognized Peters anomaly genes, we identified a de novo missense mutation in PAX6, c.155G>A, p.(Cys52Tyr), in one patient. Analysis of 691 additional genes currently associated with a different ocular phenotype identified a heterozygous splicing mutation c.1025+2T>A in TFAP2A, a de novo heterozygous nonsense mutation c.715C>T, p.(Gln239*) in HCCS, a hemizygous mutation c.385G>A, p.(Glu129Lys) in NDP, a hemizygous mutation c.3446C>T, p.(Pro1149Leu) in FLNA, and compound heterozygous mutations c.1422T>A, p.(Tyr474*) and c.2544G>A, p.(Met848Ile) in SLC4A11; all mutations, except for the FLNA and SLC4A11 c.2544G>A alleles, are novel. This is the frst study to use whole exome sequencing to discern the genetic etiology of a large cohort of patients with syndromic or isolated Peters anomaly. We report five new genes associated with this condition and suggest screening of TFAP2A and FLNA in patients with Peters anomaly and relevant syndromic features and HCCS, NDP and SLC4A11 in patients with isolated Peters anomaly.

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Section: Resultsmentioning

confidence: 99%

Whole exome sequence analysis of Peters anomaly

et al. 2014

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“…3 The combination of microphthalmia with CDH has also been reported because of deletions or variants in other genes or genomic loci. [4][5][6] Here, we investigated a familial case of syndromic microphthalmia in association with CDH, spina bifida and cardiac anomalies. To identify the cause, we performed exome sequencing on two affected male siblings and both parents, which identified a variant in the X-linked PORCN gene as the underlying cause.…”

Section: Introductionmentioning

confidence: 99%

Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia

et al. 2014

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Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non-mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range.

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“…Although HCCS is ubiquitously expressed (Schaefer et al, 1996; Schwarz & Cox, 2002), the highly specific clinical features observed in MLS affected females suggest a critical function and a sensitive dosage for HCCS in the eye and the skin. Microcephaly, mental retardation, diaphragmatic hernia and congenital heart defects are additional features less frequently observed in female patients (Morleo & Franco, 2009 [update 2011]; Sharma et al, 2008), implying that non‐random X chromosome inactivation may also influence the MLS phenotype (Franco & Ballabio, 2006; Morleo & Franco, 2008; Van den Veyver, 2001).…”

Section: Introductionmentioning

confidence: 99%

The impairment of HCCS leads to MLS syndrome by activating a non‐canonical cell death pathway in the brain and eyes

et al. 2013

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Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.

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Microphthalmia with Linear Skin Defects: A Case Report and Review

Cited by 25 publications

References 25 publications

Whole exome sequence analysis of Peters anomaly

Whole exome sequence analysis of Peters anomaly

Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia

The impairment of HCCS leads to MLS syndrome by activating a non‐canonical cell death pathway in the brain and eyes

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