A novel c.2T>A NDP missense mutation in a Chinese family with Norrie disease.

Abstract

Norrie disease (ND) is a rare X-linked recessive disorder characterized by bilateral congenital blindness in males due to deficient sprouting of the retinal vascular plexus during eye development. The majority of patients suffer from sensorineural hearing loss with an onset in childhood or early adulthood. Approximately 30–50% of patients show some degree of cognitive retardation. The Norrie disease pseudoglioma gene (NDP), located on chromosome Xp11.4, underlies ND. This gene encodes norrin that plays a critical role in retinal vascular development (Xu et al. 2004). Numerous NDP gene variants from several countries in various ethnic populations are reported in ND. We accepted a Chinese family with ND with alterations in the NDP gene by molecular genetic testing and identified a novel mutation responsible for ND. A 7-year-old boy was referred to our department to our clinic because of the impaired vision in both eyes since childhood. He had normal reference psychomotor development and normal hearing ability. His right eye had leukoma of cornea and retina was invisible. The left eye had clear cornea with deep chamber and transparent lens. Fundus examination revealed retinal detachment and absence of visible retinal vascular (Fig. 1A,B). Ultrasound B-scan showed complete retinal detachment in right eye and tractional retinal detachment in the left eye (Fig. 1C,D). His 4-year-old brother failed to follow moving light stimuli after birth. Both of his eyes had opaque corneas, posterior synechiae and dense secondary cataract. We examined the eyes of their parents, both of them are normal, and other family members we investigated do not have impaired vision. Sequence analysis of the NDP gene in the elder brother revealed a hemizygous variant at nucleotide position c.2T>A in exon 2, resulting in a missense mutation p.Met1Lys (Fig. 1E). Given this information, we tested NDP gene exon 2 of younger brother and their parents. His brother also carried this hemizygous variant (Fig. 1F) and the mother was heterozygous for the mutation (Fig. 1G). But this mutation was absent in his father (Fig. 1H). The present ND family shows a distinct genetic defect with a missense mutation at codon 2 of exon 2 of the NDP gene. Over 100 mutations have been identified, and the severity and classification of disease correlate approximately with genotype. In this case, we found a novel mutation c.2T>A in exon 2 responsible for ND resulting in a missense mutation. The mutation affecting the initiation codon produced an AAG codon, which could not initiate translation. As the translation start site and its context sequence play an important role in the control of translation efficiency and the correct translation of mRNA, the c.2T>A mutation is expected to cause the failure of the start of ND gene translation or the production of an aberrant protein. Previous reported initiation codon point mutations, c.1_2delAAT, c.2_3delTG, c.1A>G (p.Met1Val) and c.2T>G (p.Met1Arg), have been reported to be responsible for ND (Isashiki et al. 1995; Schuback et al. 1995; Caballero et al. 1996; Zhang et al. 2013). All these patients have congenital blindness. The patients with c.1_2delAAT, c.2_3delTG and c.1A>G mutation remained unremarkable in ontological and neurological studies, while the patient with c.2T>G mutation had hearing loss and autistic features. In this case, both hearing problems and mental retardation were absent in two patients. We suppose that the differences in the mutations and the subsequent differences in the translation efficiency and aberrant protein products may contribute to the differences in clinical manifestation. In summary, we reported a novel missense NDP mutation of a familial case of ND in a Chinese family.