Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice

Abstract

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development.

Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure

“…Previously, we have demonstrated that a failure to degrade HA also resulted in cardiac abnormalities in Hyal2 −/− mice and HYAL2-deficient humans. 5 , 6 Herein, we show that these abnormalities, and others, are present by 4 weeks of age and result in progressive and severe diastolic dysfunction. The persistence of HA in the absence of HYAL2 presumably promotes EMT and mesenchymal cell proliferation, resulting in excess mesenchymal cells in all Hyal2 −/− mice, providing a molecular explanation for the fibrosis, and abnormal heart structures including thickened valves and atrial masses.…”

“… 3 In humans, a single case of partial HAS2 deficiency was associated with a ventricular septal defect 24 ; a complete HAS2 deficiency is unlikely to be compatible with life. We have recently described humans with HYAL2 deficiency and demonstrated that the cardiac phenotypes, which included cor triatriatum, atrial enlargement, valvular thickening and accessory tissue, and dilated coronary sinus, 6 were similar to those in the Hyal2 −/− mice. In addition, both the humans and mice shared palate abnormalities and hearing loss.…”

“… 3 Recently, defective degradation of HA because of hyaluronidase 2 (HYAL2) deficiency was identified as a cause of cor triatriatum sinister and other heart abnormalities in both humans and mice. 4 – 6 …”

Comparative analysis of avian hearts provides little evidence for variation among species with acquired endothermy

“…Benninghoff () suggested that the myocardial shelf of birds develops from the left pulmonary ridge of the early embryonic atrium. A recent mouse model recapitulates cor triatriatum as seen in some patients, but it is not clear whether the morphology in that model is the outcome of aberrant development of the left pulmonary ridge (Muggenthaler et al, ).…”

Elsahy–Waters syndrome is caused by biallelic mutations in CDH11

“…We have attempted to address this challenge by publishing large scale tentative disease‐gene links to facilitate post‐publication matchmaking (Alazamiet al, ; Shaheen, Patel, et al, ; Shaheen, Szymanska, et al, ; Shamseldin et al, , ). This paper is one of many that resulted from a successful and quick post‐publication matchmaking (Breuss et al, ; Elo et al, ; Gai et al, ; Loucks et al, ; Muggenthaler et al, ; Palmer et al, ; Picker‐Minh et al, ; Wheway et al, ). In 2017, we briefly described the index in Family 1 as one of 35 patients each harboring a candidate mutation in 33 genes with no established link to human diseases (Anazi et al, ).…”