Familial recurrence of <i>SOX2</i> anophthalmia syndrome: Phenotypically normal mother with two affected daughters

Schneider, Adele; Bardakjian, Tanya; Zhou, Jie; Hughes, Nkecha; Keep, Rosanne; Dorsainville, Darnelle; Kherani, Femida; Katowitz, James A.; Schimmenti, Lisa A.; Hummel, Marybeth; FitzPatrick, David R.; Young, Terri L.

doi:10.1002/ajmg.a.32384

Cited by 28 publications

(35 citation statements)

References 11 publications

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“…The importance of SOX2 has been highlighted in recent literature by its involvement in reprogramming terminally differentiated cells into induced pluripotent stem cells (iPSCs) (45,64,69). Lossof-function mutations in SOX2 can cause improper eye and brain development (22,55,74,79). SOX2 downregulation in uninfected NPCs is associated with, and necessary for, both glial and neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Luo

Hannemann

Kulkarni

et al. 2010

J Virol

101

162

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Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, largely manifested as central nervous system (CNS) disorders. The principal site of manifestations in the mouse model is the fetal brain's neural progenitor cell (NPC)-rich subventricular zone. Our previous human NPC studies found these cells to be fully permissive for HCMV and a useful in vitro model system. In continuing work, we observed that under culture conditions favoring maintenance of multipotency, infection caused NPCs to quickly and abnormally differentiate. This phenotypic change required active viral transcription. Whole-genome expression analysis found rapid downregulation of genes that maintain multipotency and establish NPCs' neural identity. Quantitative PCR, Western blot, and immunofluorescence assays confirmed that the mRNA and protein levels of four hallmark NPC proteins (nestin, doublecortin, sex-determining homeobox 2, and glial fibrillary acidic protein) were decreased by HCMV infection. The decreases required active viral replication and were due, at least in part, to proteasomal degradation. Our results suggest that HCMV infection causes in utero CNS defects by inducing both premature and abnormal differentiation of NPCs.Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily affecting the central nervous system (CNS). Primary infection during pregnancy poses a 30 to 40% risk of intrauterine transmission, with severe adverse outcomes more likely if the infection occurs within the first half of gestation (46). Each year, approximately 1% of all newborns are congenitally infected with HCMV. Approximately 5 to 10% of these infants manifest signs of serious neurological defects at birth, including deafness, mental retardation, blindness, microencephaly, hydrocephalus, and cerebral calcification (2,4,65). In addition, 10 to 15% of congenitally infected infants who are asymptomatic at birth subsequently develop brain disorders such as sensorineural hearing loss (12, 47, 52). Moreover, accumulating evidence suggests that more subtle changes in human brain development, such as autism and language development, may be related to congenital HCMV infection (68,76,77).Although HCMV can infect a wide range of tissues in vivo (61), the fetal brain is the principal site of the deleterious manifestations of infection. It has been suggested that the severity of neuropathological changes and clinical outcomes may be associated with the stage of CNS development at which congenital infection occurs, with early-gestation infections producing more severe outcomes (3, 46). However, the mechanism of HCMV pathogenesis in the developing CNS remains poorly understood. Studies of HCMV in human subjects have obvious limitations; therefore, model systems of both in vitro and in vivo HCMV infections have been devised to provide insights into infection of the developing brain.Congenital infection studies have been performed principally with the mouse model. Studies of mice revealed that very ea...

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Luo

Hannemann

Kulkarni

et al. 2010

J Virol

101

162

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“…21,22 The observed spectrum also includes normal eye development in heterozygote 23 and mosaic 17,[23][24][25] /queried mosaic 26 heterozygote SOX2 mutation patients, as in the mother in this case. In addition to pituitary dysfunction, a substantial proportion of SOX2 mutation patients have other cerebral abnormalities as seen in patient II.1 in this report.…”

Section: Discussionmentioning

confidence: 95%

“…17,[23][24][25][26] These mothers have all been phenotypically normal. Our case is the first report of one such mother having IHH.…”

Section: Discussionmentioning

confidence: 99%

“…The mother, I.2 ( Figure 1a, Table 1) previously had an endocrine investigation at the age of 18 years because of primary amenorrhoea and limited development of secondary sexual characteristics. Her investigations revealed low FSH 3.5 mIU/ml (2.0-16.0), LH o3.0 mIU/ml (4.0-20.0) and oestradiol 11 pg/ml (prepubertal [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Prolactin and thyroid function tests, and a computed tomography scan of the pituitary and hypothalamus were normal.…”

Section: Clinical Findingsmentioning

confidence: 99%

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Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring

et al. 2011

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Isolated hypogonadotropic hypogonadism (IHH) is a genetically heterogeneous condition in which patients frequently require assisted reproduction to achieve fertility. In patients with IHH who are otherwise well, no particular increased risk of congenital anomalies in the resultant offspring has been highlighted. Heterozygous mutations in SOX2 are the commonest single-gene cause of anophthalmia/microphthalmia (A/M) and sometimes result in pituitary abnormalities. We report a family with a novel frameshift mutation in the SOX2 transactivation domain, p.Gly280AlafsX91, resulting in bilateral anophthalmia and subtle endocrinological abnormalities in a male sibling, and unilateral microphthalmia in a female sibling. The mutation is present in their mother who has IHH, but has no eye disorders or other anomalies. She underwent assisted reproduction to achieve fertility. This report has important implications for the evaluation of patients with IHH, particularly in the setting of planned infertility treatment.

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“…Many of the findings in this syndrome are not evident at birth. Sequencing followed by deletion studies if no mutation is identified should be considered [36,37]. In addition, parental studies and prenatal testing should be discussed with any family when a SOX2 mutation is identified.…”

Section: Key Pointsmentioning

confidence: 98%

The genetics of anophthalmia and microphthalmia

Bardakjian

Schneider

2011

Current Opinion in Ophthalmology

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The recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling.

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Familial recurrence of SOX2 anophthalmia syndrome: Phenotypically normal mother with two affected daughters

Cited by 28 publications

References 11 publications

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Human Cytomegalovirus Infection Causes Premature and Abnormal Differentiation of Human Neural Progenitor Cells

Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring

The genetics of anophthalmia and microphthalmia

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