A novel Nance-Horan syndrome mutation identified by next-generation sequencing in a Chinese family

INTRODUCTION

Nance-Horan syndrome (NHS; MIM 302350), a rare X-linked syndrome characterized by congenital bilateral cataracts and dental abnormity, was first reported in 1974 by two studies independently

. So far, this syndrome has been reported in different ethnic groups and reveal variable clinical features

. Male patients manifest severe bilateral congenital nuclear cataracts, including opacity in the fetal nucleus and posterior Y-suture; thus, surgical intervention should be performed at an early age

. Other ophthalmological abnormalities include microcornea, microphthalmia and nystagmus. Non-ophthalmic abnormalities include dental anomalies (supernumerary maxillary incisors, screwdrivershaped incisors, and diastema), mental retardation and lateral brachymetacarpalia. As an X-linked hereditary disorder,heterozygous females exhibit similar but milder features than affected males, including posterior Y-sutural cataracts, little or no loss of vision and occasional dental abnormalities

.

This family included two affected males. And all family members were further investigated for clinical features to provide precise information. Considering the unbalanced incidence between male and female members,we suggest the mode of inheritance was X-linked.

布朗預測，不用幾年，消費者將再也不會擔心基因編輯的農作物與傳統農作物之間的區別。在現代農業中，這是最具有革命性的幾次創新之一。

SUBJECTS AND METHODS

金融體系的多樣性對于整個經濟的發展有著極其重要的作用，同時也有著非同凡響的意義。而且在信息技術層次不斷發展的背景下，對于互聯網金融來說更是有著十分重要的影響作用。通過各種金融信息技術將金融資源配置、風險管理都納入到技術層次，為金融基礎體系的構建打下堅實的基礎，同時對于電子銀行、互聯網金融市場的發展有著十分正面的作用。但是，由于其本身就具有高風險的特征，結合在一起必定會為互聯網金融帶來更大的財務風險，亟待構建相應的防范體系及控制機制，才能夠為互聯網金融的穩健打下堅實的基礎。

A Chinese family(family LZ) with the initial symptom of poor central vision was recruited from the First Affiliated Hospital of Nanjing Medical University (Figure 1). Eight family members,including four affected patients and four healthy siblings,participated in our study. All included members from family LZ received ophthalmic examinations with their medical histories collected. Systemic examinations were conducted on the four patients. Another 150 unrelated healthy controls free of major ocular diseases were also recruited. Peripheral venous blood samples were collected from all participants from family LZ and 150 additionally unrelated healthy controls free of major ocular diseases using 5 mL tubes containing ethylenediamantetetraacetic acid (EDTA). Genomic DNA isolation was performed using a QIAmp DNA blood kit(Qiagen, Valencia, CA, USA) per the manufacturer’s protocols.DNA samples were stored at -20°C before used.

Our study, conformed to the tenets of the Declaration of Helsinki, was approved and prospectively reviewed by the Ethics Committee on Human Research ofNanjing Medical University. Written informed consents were signed by the participants or their legal guardians before enrollment.

The NHS gene, located on Xp22.13, is expressed during the development of embryonic tissues, especially in midbrain,lens, retina, craniofacial mesenchyme and tooth

. And it is conserved among human and other vertebrate species

.It comprises 10 exons which encompass about 650 kb of genomic DNA, and at least 4 different isoforms resulting from alternative splicing

. NHS-A and NHS-1A are the two major isoforms transcribed from exon1, encoding 1630 amino acids and 1651 amino acids respectively. NHS-B, encoding 1335 amino acids, is transcribed from exon 1b and translated from exon 4. NHS-C, encoding 1453 amino acids, is transcribed and translated from exon 1a. The exact biological function of NHS protein is unclear. To date, more than 40 mutations associated with NHS have been reported, originating from China, Australia, India, the United Kingdom, the United States of America and Turkey

. Most of the identified mutations are nonsense or indel, while others are frameshift mutations,genomic rearrangements and missense mutations

. The underlying consequence of these mutations can be classified into two categories. One is function damaging, the other is aberrant cellular distribution. In this study, the mutation in the NHS gene produced a truncated NHS protein. In most cases,the premature protein can initiate the nonsense-mediated mRNA decay pathway (NMD) which is able to degrade the shortened mRNA and protect cells from potential toxic effects resulting from dominant negative or gain-of-function effects

. Some mRNAs with PTCs, however, can avoid this translation coupled quality control system, resulting in truncated proteins. Weather this mutation is able to provide truncated protein requires further investigation. It has been reported that nonsense mutation can also lead to disrupted NH

-terminus and COOH-terminus of NHS protein resulting in aberrant intercellular location in the epithelium of lens and retinas. As NHS proteins are co-located with tight junction protein ZO-1, this loss of subcellular localization can cause disease

.Considering this mutation happened from 3916 to 3919 and NH

-terminus can act as a label for protein localization, the abnormal subcellular localization may not happen in this pedigree.

在菲律賓、馬來西亞等地區的熱帶雨林里，生活著一種長著白色“胡須”的豬——須野豬。這種被稱為“胡子豬”的豬科動物，有著棕灰色的皮毛和顯眼的“大胡子”，體長多在100—165厘米之間，為中型偶蹄目動物。

RESULTS

NHS gene locates to Xp22.31 to p22.13b between short tandem repeat markers DXS1195 and DXS999

. It is highly conserved among human and other vertebrates including rat,mouse, and zebrafish. NHS protein plays an important role in the development of ocular lens, tooth, midbrain, thus its mutations can lead to congenital cataract, dental anomalies and, in some cases, mental retardation

. Previous studies have discovered more than 40 mutations in the

gene including frameshift mutations, nonsense mutations, missense mutations,deletion mutations and genomic rearrangements

. Here,we report a novel a frameshift deletion in the

gene(c.3916_3919del) and characterize the clinical features of a Chinese pedigree with this syndrome.

NHS is an X-linked inheritance pattern involving bilateral congenital cataracts, dental anomalies and craniofacial dysmorphisms

. Mild mental retardation has been reported in about 20% of affected patients

. The proband (LZ-IV:2)and his brother (LZ-IV:1) exhibited congenital cataract with microcornea and strabismus which were similar to NHS syndrome. In order to find out the underlying causes, we performed targeted NGS, and found a novel mutation in the NHS gene. The pedigree family was recalled for further examination after this identification. The two affected males manifested characteristic ocular clinical features of NHS.Other two female carriers manifested milder signs (posterior Y-sutural cataracts). So, the results of targeted NGS as well as clinical features indicated the existence of NHS mutation in this pedigree.

二是適當放開項目承擔單位在項目預算執行調整方面的權限。政策調整前，項目單位只在勞務費、專家咨詢費和管理費以外的其他8項單項支出科目中，當預算支出科目不超出核定預算的10%、或雖然超出10%但金額不低于5萬元的預算執行調整具有自主權。政策調整后，在項目總預算不變的前提下,項目承擔單位可以自主調整直接費用中的材料費等5項開支科目的預算執行，并且沒有調整額度的限制。……