Mutation spectrum of Fork-Head Transcriptional Factor Gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients

Kaur, Inderjeet; Hussain, Avid; Naik, Milind N.; Murthy, R Ven; Honavar, Santosh G

doi:10.1136/bjo.2009.177972

Cited by 20 publications

(14 citation statements)

References 29 publications

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“…These findings are reminiscent of PCOS, the most common ovarian dysfunction in women in their reproductive life, as suggested by Murphy [61]. Although a link between FOXL2 dysregulation and PCOS has not yet been demonstrated clearly in humans, constitutional FOXL2 mutations found in syndromic POF (BPES type I) associated withandrogen-induced hirsutism [61], and in a BPES patient with reported PCOS [62] might represent first hints. However, it should be noted that PCOS is very common in the general population (6-10%) and can go up to 52% in the Indian subcontinent [63,64].…”

Section: Foxl2 Impairment In Other Diseasesmentioning

confidence: 89%

<i>FOXL2 </i>Impairment in Human Disease

Verdin¹,

Baere²

2012

Horm Res Paediatr

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FOXL2 encodes a forkhead transcription factor that plays important roles in the ovary during development and in post-natal, adult life. Here, we focus on the clinical consequences of FOXL2 impairment in human disease. In line with other forkhead transcription factors, its constitutional genetic defects and a somatic mutation lead to developmental disease and cancer, respectively. More than 100 unique constitutional mutations and regulatory defects have been found in blepharophimosis syndrome (BPES), a complex eyelid malformation associated (type I) or not (type II) with premature ovarian failure (POF). In agreement with the BPES phenotype, FOXL2 is expressed in the developing eyelids and in fetal and adult ovaries. Two knock-out mice and at least one natural animal model, the Polled Intersex Syndrome goat, are known. They recapitulate the BPES phenotype and have provided many insights into the ovarian pathology. Only a few constitutional mutations have been described in nonsyndromic POF. Moreover, a recurrent somatic mutation p.C134W was found to be specific for adult ovarian granulo-sa cell tumors. Functional studies investigating the consequences of FOXL2 mutations or regulatory defects have shed light on the molecular pathogenesis of the aforementioned conditions, and contributed considerably to genotype-phenotype correlations. Recently, a conditional knock-out of Foxl2 in the mouse induced somatic transdifferentiation of ovary into testis in adult mice, suggesting that Foxl2 has an anti-testis function in the adult ovary. This changed our view on the ovary and testis as terminally differentiated organs in adult mammals. Finally, this might have potential implications for the understanding and treatment of frequent conditions such as POF and polycystic ovary syndrome.

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Section: Foxl2 Impairment In Other Diseasesmentioning

confidence: 89%

<i>FOXL2 </i>Impairment in Human Disease

Verdin¹,

Baere²

2012

Horm Res Paediatr

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“…The low prevalence of FOXL2 mutation in our patient population could be partly attributed to a different ethnic population and very few cases with a positive family history. Previous genetic studies on Indian BPES patients have been reported from the southern parts of India, [15][16][17] where the population is ethnically different from Northern India and a high number of consanguineous marriages are found, resulting in a different mutation spectrum. In our study, seven out of nine familial cases (77%) were found to be positive for genetic defects, which is consistent with western studies in which 72% of clinically diagnosed BPES cases have a mutation in the FOXL2 gene.…”

Section: Discussionmentioning

confidence: 99%

“…Also, there have been very few genetic studies so far on the pattern of genetic abnormalities found in BPES cases in the Indian population. [15][16][17] Therefore, we undertook a prospective study at our center to evaluate BPES patients with respect to clinical, genetic, and imaging findings.…”

Section: Methodsmentioning

confidence: 99%

Clinical, Radiologic, and Genetic Features in Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome in the Indian Population

Chawla

Bhadange

Dada

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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To the best of our knowledge, this is the first study on clinical features in BPES patients of Indian origin. A high incidence of refractive error, strabismus, and amblyopia was found in BPES cases. Orbital imaging confirmed that clinical features are limited to soft tissue abnormalities, with no underlying bony changes. Cytogenetic studies showed that most chromosomal abnormalities in the Indian population are in the region of the long arm of chromosome 3. Results of molecular analysis indicate that there may be loci other than the FOXL2 gene, which are affected in BPES cases. Our study expands the existing mutation spectrum of FOXL2 gene.

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“…Goats that are recessive for this mutation show XX female-to-male sex reversal [Pailhoux et al, 2001]. Two recessive mutations have been reported, associated with BPES and ovarian failure, a phenotype identical to the dominant heterozygous mutations with no evidence of virilization [Nallathambi et al, 2007;Kaur et al, 2011]. However, in both cases, it is likely that the mutant alleles are hypomorphic, retaining some biological activity, so the phenotype of a true FOXL2 null mutation in the human remains to be determined.…”

Section: Gene Mutations Associated With 46xx Srynegative Testicular mentioning

confidence: 99%

Gene Mutations Associated with Anomalies of Human Gonad Formation

Bashamboo

McElreavey²

2012

Sex Dev

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Here, we discuss recent progress on our understanding of the genetic anomalies that impact directly on the specification and development of the somatic cell compartment of the human gonad. Several new genes and pathways have been identified in the last 5 years associated with human disorders of sex development (DSD). New methods and analytical approaches, including comparative genomic hybridization and next-generation sequencing technologies, are beginning to provide deeper insights into the complexities and alterations of the genetic architecture that are associated with human DSD. The challenges as well as the research opportunities for the future are highlighted as efforts are made to bridge the gap between an increasing quantity of genetic information and the underlying biology.

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Mutation spectrum of Fork-Head Transcriptional Factor Gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients

Abstract: Mutations in the region downstream of the fork-head domain were predominantly responsible for BPES among Indian patients.

Cited by 20 publications

References 29 publications

<i>FOXL2 </i>Impairment in Human Disease

<i>FOXL2 </i>Impairment in Human Disease

Clinical, Radiologic, and Genetic Features in Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome in the Indian Population

Gene Mutations Associated with Anomalies of Human Gonad Formation

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