The enigma of the E326K mutation in acid β-glucocerebrosidase

A large number of mutations, and several polymorphisms, have been characterized in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, the activity of which is impaired in Gaucher disease. In this communication we summarize published and new data concerning biochemical characterization of the E326K amino acid change (1093G>A in the GBA1 cDNA) in tissue culture and its association with Parkinson disease, suggesting it is a disease causing mutation and not merely a polymorphism in the GBA gene.     

The in vitro motility activity of β-cardiac myosin depends on the nature of the β-myosin heavy chain gene mutation in hypertrophic cardiomyopathy

Several mutations in the -myosin heavy chain gene cause hypertrophic cardiomyopathy. This study investigates (1) the in vitro velocities of translocation of fluorescently-labelled actin by -myosin purified from soleus muscle of 30 hypertrophic cardiomyopathy patients with seven distinct -myosin heavy chain gene mutations: Thr124Ile, Tyr162Cys, Gly256Glu, Arg403Gln, Val606Met, Arg870His, and Leu908Val mutations; and (2) motility activity of -myosin purified from cardiac and soleus muscle biopsies in the same patients. The velocity of translocation of actin by -myosin purified from soleus or cardiac muscle of 22 normal controls was 0.48 ± 0.09 m s–1. By comparison, the motility activity was reduced in all 30 patients with -myosin heavy chain gene mutations (range, 0.112 ± 0.041 to 0.292 ± 0.066 m s–1). Notably, the Tyr162Cys and Arg403Gln mutations demonstrated significantly lower actin sliding velocities: 0.123 ± 0.044, and 0.112 ± 0.041 m s–1, respectively. -myosin purified from soleus muscle from four patients with the Arg403Gln mutation had a similar actomyosin motility activity compared to -myosin purified from their cardiac biopsies (0.127 ± 0.045 m s–1 versus 0.119 ± 0.068 m s–1, respectively). Since these seven mutations lie in several distinct functional domains, it is likely that the mechanisms of their inhibitions of motility are different     

A case of β-Thalassemia with rare gene mutation and the tamily analysis

目的 鉴定1种罕见的β地中海贫血突变类型.方法 血液学分析采用血细胞分析仪及全自动快速电泳分析系统;α珠蛋白常规突变检测采用Gap-PCR;β珠蛋白常规突变检测采用反向点杂交法;样品的基因突变及基因型用β珠蛋白基因全长测序技术确定.结果 先证者具有典型的β地中海贫血临床特点和血液学特性,HbF为5.8％,其父母各项指标均正常.未发现先证者及其家庭成员有已知的α-/β-地中海贫血基因突变,测序发现先证者及其母亲均为CD2 (CAT-CAC)杂合子,父亲为CAC纯合子;先证者有β珠蛋白exon1 CD27 (GCC-GAC)突变,编码的氨基酸由丙氨酸变为天冬氨酸,未发现其父母有CD27突变.结论 CD27 (GCC-GAC)突变是罕见的β珠蛋白基因点突变,有助于指导人群筛查、遗传咨询和临床诊断.     

Correlation of the antiseptic resistance in Acinetobacter baumannii and the antiseptic resistance gene qacE Δ 1 located in class Ⅰ integron

In the past decade, uses of antiseptics and disinfectants in hospitals and other health care centers are rather common, but the chance to develop resistance to antiseptics and disinfectants is also increased. Acinetobacter baumannii is one of the opportunistic bacteria involving in the nosocomial infection . In the present study, the correlation of the antiseptic resistance in A . baumannii and the antiseptic resistance gene qacEΔ1 was investigated by means of determination of MICs. Meanwhile, the MICs of glutaraldehyde, chlorhexidine, benzalkonium bromide, iodophor and trichloroisocyanurate to 80 clinical isolates of A. baumannii were detected by tube dilution assay and the resistance genes intI1 and qacEΔ1 in these isolates were amplified by PCR and verified by DNA sequencer. It was found that the MIC50 for these 5 antiseptics tested were 32, 8, 8, 4 and 1μg/ml respectively, and the detection rates of intI1 and qacEΔ1 gene were 60.0% and 77.6% respectively. In addition, 55% of the 80 isolates simultaneously possessed both intll and qacEΔ1 gene, and the percentage of antiseptic resistance of A . baumannii carring both genes to benzalkonium bromide were higher than that without these two genes, however, there was no significant difference between intll and qacEΔ1 gene. The result in bactericidal efficiency assay indicated that chlorhexidine could still produce rapid and strong bactericidal effect at concentration of 1 MIC after 10 min exposure. These results suggest that the antiseptic resistance of A . baumannii to various antiseptics is correlated with the presence of the antiseptic resistance genes qacEΔ1 in bacteria, thus warning that the increase of the antiseptic resistance should not be ignored and the relative high concentration or prolonged application time is required to achieve a sufficient bactericidal effect.     

Amino-acid alterations in the β-tubilin gene of Neurospora crassa that confer resistance to carbendazim and diethofencarb

We have previously shown that increased sensitivity to diethofencarb in the carbendazim(MBC)-resistant F914 strain of Neurospora crassa is caused by a single amino-acid change in -tubulin, ¹⁹⁸Glu to Gly. Three diethofencarb-resistant mutants that are also resistant to MBC were isolated from strain F914. They contained single base-pair-substitution mutations in the -tubulin gene. The amino acid changes in -tubulin, Phe from ²⁵⁰Leu, Val from ¹⁶⁵Ala, and Ala from ²³⁷Thr, were responsible for diethofencarb-resistance in the mutant strains FR511, FR513, and FR421, respectively. The amino acid at position 198 of -tubulin in these mutants was Gly, which is the same as in strain F914. -tubulin genes with ¹⁹⁸Glu were constructed by site-directed mutagenesis. The altered -tubulin genes derived from FR511 and FR421 transformed the wild-type strain to resistance to MBC, indicating that ²⁵⁰Phe and ²³⁷Ala in -tubulin are responsible for resistance not only to diethofencarb but also to MBC.     

Extreme androgen resistance in a kindred with a novel insertion/deletion mutation in exon 5 of the androgen receptor gene

Androgen insensitivy syndrome (AIS) is the most frequent cause of male pseudohermaphroditism resulting from target-organ resistance to androgen action. Individuals bearing the complete form of the disease (CAIS) present a female phenotype and a lack of pubic and axillary hair. In the present study, four 46,XY patients born in two generations from a kindred with a history of AIS were examined for genetic abnormalities in the androgen receptor gene (AR). All eight exons encoding the AR protein were individually amplified from genomic DNA followed by a mutation screening with single-strand conformation polymorphism analysis. Sequencing of the mutant AR revealed a novel insertion/deletion mutation in exon 5. A deletion of 7 bp is replaced by an insertion of 11 nucleotides, which represents a duplication of the adjacent downstream sequence. The mutation g.2640_2646delAGGATGC/2652_2662insTTCGCCCCTGA, results in a frameshift that introduces a premature termination signal TGA, nine codons downstream. Such a rearrangement predicts a truncation of the AR, thereby deleting a large portion of the ligand-binding domain (amino acid position 768–919). Furthermore, although this mutation breaks the translational reading frame starting from codon 760, examination of the complementary DNA suggested that it does not disturb mRNA splicing. These changes have been found in all the patients and appear to account for the observed absence of detectable androgen binding to the AR in cultured fibroblasts and for the CAIS phenotype in the kindred. This disorder represents the first insertion/deletion mutation of the AR that probably arose by a slipped-strand mispairing mechanism.     

Single nucleotide polymorphisms in β-tubulin selected in Onchocerca volvulus following repeated ivermectin treatment: possible indication of resistance selection

The control of onchocerciasis or river blindness by mass treatment of the population with ivermectin (IVM) has been a great success until now, so that in certain foci its elimination has become feasible. However, after more than 20 years of repeated IVM mass treatment, the disease still persists in many endemic countries. Sub-optimal responses and genetic changes have been reported in Onchocerca volvulus populations under high IVM pressure but more work is needed to determine whether resistance is developing. The situation needs to be urgently clarified to preserve the achievements of onchocerciasis control programs. In this study, O. volvulus adult worms were collected from the same individuals, before IVM exposure and following three years of annual or three-monthly treatments at 150 μg/kg or 800 μg/kg. Four single nucleotide polymorphisms (SNPs) occurring in the β-tubulin gene of these parasites were investigated. We found changes in genotype frequencies in O. volvulus β-tubulin gene associated with IVM treatments. The SNP at position 1545 (A/G) showed a significant increase in frequency of the less common nucleotide in the female worms following treatment. After 13 three-monthly treatments, female worm homozygotes with the less common genotype, prior to treatment, increased in frequency. The selected homozygotes, as well as heterozygotes, appeared to be less fertile (without or with very few embryonic stages in their uteri) than the wild-type homozygotes. These results provide additional evidence for genetic selection and strengthen the warning that selection for IVM resistance may be occurring in some O. volvulus populations.     

Importance of Conserved Residues of the Serine Protease Autotransporter β-Domain in Passenger Domain Processing and β-Barrel Assembly

Serine protease autotransporters of the family Enterobacteriaceae (SPATE) comprise a family of virulence proteins secreted by enteric Gram-negative bacteria via the autotransporter secretion pathway. A SPATE polypeptide contains a C-terminal translocator domain that inserts into the bacterial outer membrane as a β-barrel structure and mediates secretion of the passenger domain to the extracellular environment. In the present study, we examined the role of conserved residues located in the SPATE β-barrel-forming region in passenger domain secretion. Thirty-nine fully conserved residues in Tsh were mutated by single-residue substitution, and defects in their secretion phenotypes were assessed by cell fractionation and immunochemistry. A total of 22 single mutants exhibited abnormal phenotypes in different cellular compartments. Most mutants affecting secretion are charged residues with side chains pointing into the β-barrel interior. Seven mutants showed notable abnormalities in processing (constructs with the E1231A, E1249A, and R1374A mutations) and β-barrel assembly or insertion into the outer membrane (constructs with the G1158Y, F1360A, Y1375A, and F1377A mutations). The phenotypes of the β-barrel assembly/insertion mutants and the presence of a processed Tsh passenger domain in the periplasm support the possibility that the translocator domain must undergo extensive folding prior to insertion into the outer membrane. Results from double-mutation experiments further demonstrate that F1360 and F1377 affect β-barrel insertion/assembly at different times. In light of these new data, a more refined model for the mechanism of SPATE secretion is presented.In Gram-negative bacteria, the type V, or autotransporter (AT), pathway is among the most commonly utilized protein secretion pathways (14). A nascent AT polypeptide consists of an N-terminal signal sequence involved in inner membrane (IM) translocation, a passenger domain to be secreted to the extracellular environment, and a C-terminal translocator domain further comprised of an N-terminal α-helical linker and a C-terminal β-domain (14, 20). Following its IM translocation mediated by the Sec translocase and the removal of the signal peptide by the signal peptidase, an AT is released into the periplasm (14, 20). The extent of AT folding in the periplasm is still under investigation, although recent evidence suggests the presence of some tertiary structure in this compartment (2, 12, 16, 32) and the involvement of periplasmic chaperones in the secretion event (11, 25, 28). After an AT transits through the periplasm, the outer membrane (OM) assembly Bam (YaeT/Omp85) complex assists in an AT insertion into the OM (15, 37); there the AT translocator domain forms a pore-like β-barrel. In conventional ATs, only a single protein''s translocator domain is required to form a complete β-barrel (14). In the OM, the β-barrel tethers the folded passenger domain via the flexible α-helical linker (6, 14, 20). In many cases, the tethered passenger domain is eventually cleaved and released from the cell surface (6, 14, 20).Most ATs characterized to date possess virulence functions (6). Among the numerous conventional ATs is a subfamily named the serine protease ATs of the family Enterobacteriaceae (SPATE), which is a group of multifunctional ATs implicated in the pathogenicity of enteric bacterial pathogens (44). SPATE share many conserved elements: all of these ATs possess a requisite serine protease motif [GDSGS(P)] in the passenger domain and an α-helical linker motif (EVNNLNKRMGDLRD) in which the double asparagines serve as the cleavage site between the passenger and translocator (6, 18). Cleavage releases a SPATE into the extracellular environment, its final secretion destination (44). Considering the ubiquity of conventional ATs in pathogenic bacteria and their participation in disease development (6), a better understanding of their secretion mechanism might help improve current therapeutic means. To study the secretion mechanism of conventional ATs, we used the temperature-sensitive hemagglutinin (Tsh), a SPATE from avian-pathogenic Escherichia coli, as a model (24).This study focused on a conventional AT''s translocator domain, which has been shown to be essential for the secretion of the passenger domain (23). The crystal structure of the translocator domain of a SPATE protein, EspP, revealed a β-barrel formed by 12 antiparallel β-strands, with the α-helical linker plugging the interior of the β-barrel (1). While these features of the EspP translocator resemble those of the crystallized translocator domain of NalP (22), the processing sites between the passenger and translocator in these two ATs are remarkably different. In NalP the processing site is close to the opening of the β-barrel, and thus, the α-helical linker extends throughout the length of the channel (22). In contrast, cleavage in EspP is assisted by an aspartate residue located in the midlength of the β-barrel through autoproteolysis (3), hence leaving only half of the α-helical linker in the β-barrel (1). Autoproteolytic release of the passenger domain is unique, and the processing of other ATs requires OM proteases (5, 31), the GDSGS motif located in the passenger (8, 23), or other unknown factors.Considering the different roles of the translocator domain in an AT''s secretion process, it is possible that residues located in the translocator have different secretion functions. For instance, some residues might be the recognition sites for OM assembly factors or periplasmic chaperones; some might play a structural role stabilizing the β-barrel in the OM; and others might be responsible for promoting the processing of the passenger domain, as seen in EspP (3). Indeed, a number of residues within the conserved α-linker motif have been shown by this laboratory to be vital for passenger secretion (18). Here, we focus on the remaining region of the SPATE translocator, the β-domain. Mutations introduced into residues in this domain resulted in many defective phenotypes related to passenger secretion. Notably, several mutants impaired processing of the Tsh passenger domain, and some prevented proper assembly or insertion of the β-domain into the OM. Two key residues involved in the assembly/insertion of the β-barrel at different times were also identified. Based on our results, as interpreted in conjunction with recently published structural and biochemical data, we have proposed a more refined model for the SPATE secretion mechanism.     

Molecular genetic analyses of β-thalassemia in South India reveals rare mutations in the β-globin gene

-thalassemia is the most prevalent single-gene disorder. Since no viable forms of treatment are available, the best course is prevention through prenatal diagnosis. In the present study, the prevalence of -thalassemia was extensively investigated in the South Indian population, especially from the state of Andhra Pradesh. Screening for causal mutations was carried out on genomic DNA isolated from patient blood samples by using the routine reverse dot blot (RDB) and amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) techniques. DNA sequencing was performed wherever necessary. Among the nine mutations identified, four, including IVS-1-5 (G-C) (IVS1+5G>T), codon 41/42 (-TTCT) (c.124_127delTTCT), codon 15 (G-A) (c.47G>A), and HbS (sickle mutation) (c.20A>T) mutations, accounted for about 98% of the total positive cases. Two mutations viz. codon 8/9 (+G) (c.27_28insG) and HbE (codon 26 G-A) (c.79G>A) exhibited a very low frequency of occurrence, whereas the IVS-1-1 (G-T) (IVS1+1G>T) and the 619 bp deletion (c.366_494del) mutations were absent. We also identified certain rare mutations during the diagnostic evaluation. Gene sequencing confirmed the codon 30 (G-C) (c.92G>C) mutation and the rare codon 5 (-CT) (c.17_18delCT) and IVS-II-837 (T-G) (IVSII-14T>G) mutations. This is the first report of the IVS II 837 mutation in the Indian population. We also report a novel diagnostic application during RDB-based screening for the detection of the (c.92G>C) mutations. Such a comprehensive mutation screening is essential for prenatal diagnosis of -thalassemia and control of this highly prevalent monogenic disorder in the Indian population.     

Analysis of clinical phenotype and ACAT1 gene mutation in a family affected with β-ketothiolase deficiency北大核心CSCD

Objective: To investigate the clinical phenotype and ACATI gene mutation in a family affected with β-ketothiolase deficiency (BKTD). Methods: Clinical features and laboratory test data were collected. The probands were monozygotic twin brothers. Genomic DNA was isolated from peripheral blood leukocytes obtained from the probands and their family members. Molecular genetic testing of the ACAT1 gene was carried out. Results: The probands have presented with fever, vomiting and severe ketoacidosis. By arterial blood gas testing, pH was determined to be 7. 164, bicarbonate was 4. 0 mmol/L, and urine ketone was + + + +. Urinary organic acid gas chromatography-mass spectrometry analysis showed excessive excretion of 3-hydroxybutyric acid, 2-methyl-3-hydroxybutyric acid and tiglylglycine. Increased 3-hydroxybutyrylcarnitine (C4-OH), tiglylcarnitine (C5:1) and 3-hydroxyisovalerylcarnitine (C5-0H) levels. The clinical phenotype of proband's parents were both normal, but an elder sister turned out to be an affected patient. Genetic analysis has identified two heterozygous mutations [c. 622C>T(p. R208X) and c. 653C>T(p. S218F)] in the proband, which were respectively detected in the mother and father. The c. 653C>T(p. S218F) mutation was not found among the 100 healthy controls and has not been included in the Human Gene Mutation Database (HGMD). Conclusion: The primary clinical manifestations of BKTD is ketoacidosis. Urine organic acid and blood acylcarnitine analyses play an important role in the diagnosis of the disease. The compound heterozygous of ACAT1 gene mutations probably underlie the BKTD in our patient. © 2016, West China University of Medical Sciences. All rights reserved.     

Analysis and manipulation of neuronal gene expression using the Tα1 α-tubulin promoter

Analysis of the molecular genetic mechanisms underlying neuronal differentiation in mammals has been hampered by the lack of appropriate model systems. Here, we review the evidence that the Tα1 α-tubulin gene represents such a model system. The endogenous Tα1 gene is expressed at highly abundant levels during the growth of developing and mature neurons. In transgenic mice, 1·1 kb of 5′ flanking sequence from the Tα1 gene is sufficient to target gene expression to early developing neurons, and to regulate levels of expression as a function of neuronal growth. Analysis of this promoter has led to the initial elucidation of sequence elements essential for gene expression during neuronal development. Moreover, the Tα1 promoter provides an experimental mechanism for the manipulation and analysis of differentiating neurons in transgenic mice.     

Critical amino acid variants in HLA-DRB1 allotypes in the development of Graves’ disease and Hashimoto’s thyroiditis in the Japanese population

The effects of amino acid variants encoded by human leukocyte antigen (HLA) class II on the development of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) have not been fully elucidated. We investigated the HLA-DRB1 genes of 243 GD patients and 82 HT patients in the Japanese population and compared the frequencies of HLA-DRB1 alleles and HLA-DRB1 amino acid variants between these patients and the Japanese populations previously reported by another institution. The frequencies of HLA-DRB1*04:05 and -DRB1*14:03 alleles were significantly higher and those of HLA-DRB1*01:01 and -DRB1*15:02 alleles were lower in GD patients than in controls. The frequencies of HLA-DRB1*08:03 and -DRB1*09:01 alleles were significantly higher and that of the HLA-DRB1*13:02 allele was lower in HT patients than in controls. A blind association analysis with all amino acid positions identified DRß9 and DRß31 for GD and DRß9, DRß13, and DRß21 for HT. The frequency of Glu-9 was significantly higher and that of Cys-9 was lower in GD patients than in controls. The frequencies of Lys-9 and Phe-13 were significantly higher in HT patients than in controls. DRß9 and DRß13 could be critical amino acid positions in the development of GD and HT.     

Characterisation of a β-tubulin gene from the monogenean parasite,<Emphasis Type="Italic"> Gyrodactylus salaris</Emphasis> Malmberg, 1957

The cDNA and two partial genomic sequences of -tubulin genes have been isolated from the monogenean parasite Gyrodactylus salaris. The cDNA sequence is not represented by either of the genomic sequences, implying that at least three isotypes of the gene exist in G. salaris. The sequences show regions of high homology with other helminth -tubulin genes. This represents the first isolation of a -tubulin gene from a monogenean and contributes to the overall characterisation of these genes within the helminths. This is an important area, as anthelmintic resistance is increasing against benzimidazole drugs that target the -tubulin gene. Benzimidazole drugs have been tested successfully against Gyrodactylus parasites, but their use is not widespread. Should it increase, analysis of the -tubulin gene may provide a tool for monitoring resistance development and improving management practises. Use of the -tubulin gene in the identification of Gyrodactylus species may prove complex due to the presence of different isotypes.     

Liddle's syndrome caused by a novel mutation of the γ-subunit of epithelial sodium channel gene SCNN1G in Chinese

Objective To screen the mutation of the β and γ subunits of epithelial sodium channel gene SCNN1 in two families with Liddle's syndrome. Methods Two patients clinically diagnosed as Liddle's syndrome and their family members were enrolled. Peripheral blood samples were collected and total genomic DNA was prepared. Polymerase chain reaction (PCR) was used to amplify the exon 13 of the SCNN1B and SCNN1G gene. PCR products were purified and subjected to direct DNA sequencing. Results A heterozygous nonsense mutation at codon 564 of the SCNN1B gene from CGA(Arg) to stop codon(TGA)was detector in the proband of family 1. More importantly, a novel heterozygous nonsense mutation of CAG (Gln) to stop codon TAG at codon 567 of the SCNN1G gene was detected in the proband and another two members of family 2. Conclusion Screening for specific mutations of the SCNN1 gene in relatives of patients with Liddle's syndrome can be used to identify the previously unrecognized cases within the family.A new nonsense mutation(Q567X) of the SCNN1G gene is likely the cause of Liddle's syndrome in family 2.     

Mutant ftsI genes in the emergence of penicillin-binding proteinmediated β-lactam resistance in Haemophilus influenzae in Norway

The most important mechanism for β-lactam resistance in β-lactamase-negative ampicillin-resistant (BLNAR) isolates of Haemophilus influenzae is the alteration of penicillin-binding protein 3 (PBP3) as a result of ftsI gene mutations. The present study aimed to map PBP3 alterations and to determine the correlation to β-lactam resistance in respiratory tract isolates of H. influenzae in Norway, as well as assess the contribution of clonal spread to the emergence of PBP3-mediated resistance. Twenty-three β-lactamase negative respiratory tract isolates with resistance to penicillins and 23 susceptible control isolates were examined by determination of β-lactam MICs, ftsI sequencing and molecular typing by pulsed-field gel electrophoresis (PFGE). Ampicillin MIC ranges in the resistant group and the control group were 1–2 mg/L and 0.125–0.5 mg/L, respectively. All isolates in the resistant group had the PBP3 substitution Asn526 → Lys and were thus categorized as group II low-BLNAR. No control isolate met the genetic BLNAR (gBLNAR) criteria. The PBP3 substitution patterns corresponded well to those observed in previous European studies. Eighty-three percent (19/23) of the resistant isolates belonged to two clones, demonstrating the capability of low-BLNAR strains of clonal dissemination. Combined analysis of ftsI DNA sequences and PFGE patterns revealed distinctly different ftsI alleles in genetically indistinguishable isolates and identical copies of the same ftsI allele in unrelated isolates. A possible explanation of this observation is the recombinational exchange of ftsI alleles. This phenomenon, as well as the possibility of endemic European gBLNAR strains, should be further investigated.     

Liddle's syndrome caused by a novel mutation of the γ-subunit of epithelial sodium channel gene SCNN1G in Chinese

Objective To screen the mutation of the β and γ subunits of epithelial sodium channel gene SCNN1 in two families with Liddle's syndrome. Methods Two patients clinically diagnosed as Liddle's syndrome and their family members were enrolled. Peripheral blood samples were collected and total genomic DNA was prepared. Polymerase chain reaction (PCR) was used to amplify the exon 13 of the SCNN1B and SCNN1G gene. PCR products were purified and subjected to direct DNA sequencing. Results A heterozygous nonsense mutation at codon 564 of the SCNN1B gene from CGA(Arg) to stop codon(TGA)was detector in the proband of family 1. More importantly, a novel heterozygous nonsense mutation of CAG (Gln) to stop codon TAG at codon 567 of the SCNN1G gene was detected in the proband and another two members of family 2. Conclusion Screening for specific mutations of the SCNN1 gene in relatives of patients with Liddle's syndrome can be used to identify the previously unrecognized cases within the family.A new nonsense mutation(Q567X) of the SCNN1G gene is likely the cause of Liddle's syndrome in family 2.     

Lysosomal storage disease in the brain: mutations of the β-mannosidase gene identified in autosomal dominant nystagmus

PurposeGenetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network.MethodsPatients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. β-Mannosidase activities were measured. Gene expression, protein–protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed.ResultsA novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal β-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of β-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain.ConclusionThis is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because β-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD-associated genes in the pathogenesis of infantile nystagmus.