A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome

Pohl, Esther; Aykut, Ayça; Beleggia, Filippo; Karaca, Emin; Durmaz, Burak; Keupp, Katharina; Arslan, Esra; Onay, Melis Palamar; Yiğit, Gökhan; Özkınay, Ferda; Wollnik, Bernd

doi:10.1007/s00439-013-1337-9

Cited by 51 publications

(61 citation statements)

References 29 publications

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“…8 The authors demonstrated that the missense mutation segregating with the disease was a 11 The mouse model strongly support that PAX1 depletion in our patients caused thymus aplasia responsible of the SCID. However, after exome data filtering in the patient and his parents, 32 possibly deleterious homozygous variants remained, but none of them was a strong candidate gene for a myopathy (Table S1, Supporting information).…”

Section: Introductionsupporting

confidence: 58%

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency

et al. 2017

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Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of OFCS and a homozygous missense mutation in PAX1 gene has been described. We report whole exome sequencing of 4 members of a consanguineous family in which 2 children, showing features of OFCS, expired from severe combined immunodeficiency (SCID). To date, the co-occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for SCID. This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where SCID might represent the main feature.

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Section: Introductionsupporting

confidence: 58%

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency

et al. 2017

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“…For example, an association with nasal width was observed at 20p11.22 near the PAX1 gene. Mutations in PAX1 cause otofaciocervical syndrome [46], characterized by facial dysmorphology, including specific nasal features such as a sunken nasal root and excessive narrowing. PAX1 plays a role in chondrocyte differentiation [47], which may explain its association with nasal width, a measure of the distance between the left and right cartilaginous nasal alae.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

et al. 2016

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Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10−8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

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“…Surprisingly, lacrimal gland defects have not been reported in human aniridia (OMIM 106210), a congenital disorder caused by heterozygous mutations in PAX6 . Instead, patients with otofaciocervical syndrome-2 carrying homozygous PAX1 mutations (OMIM 615560) display lacrimal duct abnormalities, a phenotype shared with the closely related otofaciocervical syndrome-1 (OMIM 601653) that harbors mutations in the EYA1 gene (Pohl et al, 2013). On the other hand, branchiootorenal syndrome-1 (BOR1, OMIM #113650) caused by heterozygous EYA1 mutations and branchiootic syndrome-3 (OMIM #608389) caused by SIX1 heterodeficiency display many overlapping phenotypic traits including lacrimal gland stenosis, suggesting that these two genes may act in the same genetic cascade.…”

Section: The Molecular Mechanism Of Lacrimal Gland Developmentmentioning

confidence: 99%

Lacrimal gland development: From signaling interactions to regenerative medicine

Garg

Zhang

2017

Developmental Dynamics

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The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease.

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A hypofunctional PAX1 mutation causes autosomal recessively inherited otofaciocervical syndrome

Cited by 51 publications

References 29 publications

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency

A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency

Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

Lacrimal gland development: From signaling interactions to regenerative medicine

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