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

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

Design Methodology of N-Path Filters with Adjustable Frequency, Bandwidth, and Filter Shape

In this paper, an adaptive N-path filter design technique is presented. The filter designed by this method can be reconfigured to different shapes, e.g., Butterworth or Chebyshev with variable bandwidth (BW), based on the user requirements. In addition, an analytical synthesis procedure is introduced to realize high-order bandpass filters (BPFs) based on N-path architecture with a prescribed set of specifications. A proof-of-concept BPF is fabricated and measured in a 65-nm CMOS process. The filter can be reconfigured to realize different filter shapes by changing coupling capacitors. The BW of the proposed filter is also tunable. The passband of the filter is tunable from 0.2 to 1.2 GHz with a gain of 14.5-18 dB, a noise figure of 3.7-5.5 dB, and a total power consumption of 37.5-52.7 mW. The channel BW can be varied from 20 to 40 MHz and the filter out-of-band third-order intercept point (Δ f=50 MHz) is 25 dBm

Clinical findings of individuals homozygous for <i>HYAL2</i> mutations

<p>Clinical findings of individuals homozygous for <i>HYAL2</i> mutations</p

Pedigrees, clinical features of individuals homozygous for <i>HYAL2</i> mutation and identified <i>HYAL2</i> mutations, expression of wild type (WT), K148R-HYAL2 and P250L-HYAL2.

<p>(A) Pedigree diagrams and facial phenotype of individuals (Amish Family 1: XII:7; XII:9; XII:12 and Saudi Family 2: VI:2) with HYAL2 deficiency. Note the craniofacial similarities including frontal bossing, hypertelorism, widened nasal bridge, flattened broad nasal tip and cupped ears/overfolding of the superior helices. Consent for publication of these photographs was obtained (B) Electropherograms showing the identified c.443A>G & c.749C>T mutations and conservation of protein sequence across species.(C) Expression of wild type (WT), K148R and P250L-HYAL2. Western blots were performed on lysates prepared from MEFs deficient in HYAL2 that were transfected with empty vector, pCMV6-HYAL2, pCMV6-HYAL2K148R, or pCMV6-HYAL2P250L. An arrow indicates HYAL2. HYAL2 levels shown in the graph were quantified by imaging the chemiluminescent signal using a BioRad ChemiDoc. The columns represent the average level (x 10⁶ light units) of HYAL2 ± SEM (n = 4). Significance was determined using the student’s T test. *** indicates p<0.0001.</p