New recessive compound heterozygous variants of RP1L1 in RP1L1 maculopathy

AIM:To identify a maculopathy patient caused by new recessive compound heterozygous variants in RP1L1.METHODS:Comprehensive retinal morphological and functional examinations were evaluated for the patient with RP1L1 maculopathy.Targeted sequence capture array technique was used to screen potential pathologic variants.Polymerase chain reaction and Sanger sequencing were used to confirm the screening results.RESULTS:Fundus examination showed round macular lesions appeared in both eyes.Optical coherence tomography showed that the inner segment/outer segment continuity was disorganized and disruptive in the left eye,but it was uneven and slightly elevated in the right eye.Fundus autofluorescence showed patchy hyper-autofluorescence in the macula.Visual field examination indicates central defects in both eyes.Electroretinogram(ERG)and multifocal ERG showed no obvious abnormalities.Fundus fluorescein angiography in the macula showed obviously irregular hyper-fluorescence in the right eye and slightly hyper-fluorescence in the left eye.We found that the proband carried a missense variant(c.1972C>T)and a deletion variant(c.4717_4718del)of RP1L1,which were originated from the parents and formed compound heterozygous variants.Both variants are likely pathogenic according to the ACMG criteria.Multimodal imaging,ERG and detailed medical history are important diagnostic tools for differentiating between acquired and inherited retinal disorders.CONCLUSION:A maculopathy case with detailed retinal phenotype and new recessive compound heterozygous variants of RP1L1 is identified in a Chinese family,which expands the understanding of phenotype and genotype in RP1L1 maculopathy.

Detection of Novel BEST1 Variations in Autosomal Recessive Bestrophinopathy Using Third-generation Sequencing

Objective:Autosomal recessive bestrophinopathy(ARB),a retinal degenerative disease,is characterized by central visual loss,yellowish multifocal diffuse subretinal deposits,and a dramatic decrease in the light peak on electrooculogram.The potential pathogenic mechanism involves mutations in the BEST1 gene,which encodes Ca2+-activated Cl−channels in the retinal pigment epithelium(RPE),resulting in degeneration of RPE and photoreceptor.In this study,the complete clinical characteristics of two Chinese ARB families were summarized.Methods:Pacific Biosciences(PacBio)single-molecule real-time(SMRT)sequencing was performed on the probands to screen for disease-causing gene mutations,and Sanger sequencing was applied to validate variants in the patients and their family members.Results:Two novel mutations,c.202T>C(chr11:61722628,p.Y68H)and c.867+97G>A,in the BEST1 gene were identified in the two Chinese ARB families.The novel missense mutation BEST1 c.202T>C(p.Y68H)resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1.Another novel variant,BEST1 c.867+97G>A(chr11:61725867),located in intron 7,might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators.Conclusion:Our findings represent the first use of third-generation sequencing(TGS)to identify novel BEST1 mutations in patients with ARB,indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes.The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population.

Novel approach of ultrasound-guided lateral recess block for a patient with lateral recess stenosis: A case report

BACKGROUND Ultrasound guide technology,which can provide real-time visualization of the needle tip and tissues and avoid many adverse events,is widely used in mini-mally invasive therapy.However,the studies on ultrasound-guided Lateral recess block(LRB)are limited,this is probably because there is no recognized standard method for ultrasound scanning.This study aimed to evaluate the effect of ultrasound-guided LRB in patients with lateral recess stenosis(LRS).CASE SUMMARY A 65-year-old patient complained of low back pain accompanied occasionally by pain and numbness in the left lower limb.Physical examination showed ten-derness on the spinous process and paraspinal muscles from L1 to S1,extensor hallucis longus and tibialis anterior weakness(muscle strength:4-),and a positive straight leg raising test in the left lower limb(60°).Magnetic resonance imaging showed L4–L5 disc degeneration with left LRS and nerve root entrapment.Subsequently,the patient was diagnosed with LRS.This patient was treated with a novel ultrasound-guided LRB approach.The patient’s symptoms significantly improved without any complications at 1 wk postoperatively and at the 3-month follow-up.CONCLUSION This is the first report on the LRS treatment with ultrasound-guided LRB from the contralateral spinous process along the inner side of the articular process by out-plane technique.Further studies are expected to investigate the efficacy and safety of ultrasound-guided LRB for patients with LRS.

Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7:A case report

BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebellar ataxia,pyramidal signs,neurocognitive impairment,deep paresthesia,and cerebellar atrophy.CASE SUMMARY Here,we describe a 25-year-old female patient in China who presented with increasing difficulty walking,falling easily,shaking limbs,instability holding items,slurred speech,coughing when drinking,palpitations,and frequent hunger and overeating.Magnetic resonance imaging showed cerebellar atrophy.Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene:c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg.Considering the patient’s clinical presentation and genetic test results,we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency,which may lead to SCAR7.CONCLUSION We report the first case of SCAR7 from China.We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7,expanding the range of known disease-causing mutations for SCAR7.

Comprehensive analysis of glacier recession(2000-2020)in the Nun-Kun Group of Glaciers,Northwestern Himalaya

Himalayan glaciers are shrinking rapidly,especially after 2000.Glacier shrinkage,however,shows a differential pattern in space and time,emphasizing the need to monitor and assess glacier changes at a larger scale.In this study,changes of 48 glaciers situated around the twin peaks of the Nun and Kun mountains in the northwestern Himalaya,hereafter referred to as Nun-Kun Group of Glaciers(NKGG),were investigated using Landsat satellite data during 2000-2020.Changes in glacier area,snout position,Equilibrium Line Altitude(ELA),surface thickness and glacier velocity were assessed using remote sensing data supplemented by field observations.The study revealed that the NKGG glaciers have experienced a recession of 4.5%±3.4%and their snouts have retreated at the rate of 6.4±1.6 m·a^(-1).Additionally,there was a 41%increase observed in the debris cover area during the observation period.Using the geodetic approach,an average glacier elevation change of-1.4±0.4 m·a^(-1)was observed between 2000 and 2012.The observed mass loss of the NKGG has resulted in the deceleration of glacier velocity from 27.0±3.7 m·a^(-1)in 2000 to 21.2±2.2 m·a^(-1)in 2020.The ELA has shifted upwards by 83.0±22 m during the period.Glacier morphological and topographic factors showed a strong influence on glacier recession.Furthermore,a higher recession of 12.9%±3.2%was observed in small glaciers,compared to 2.7%±3.1%in larger glaciers.The debris-covered glaciers showed lower shrinkage(2.8%±1.1%)compared to the clean glaciers(9.3%±5%).The glacier depletion recorded in the NKGG during the last two decades,if continued,would severely diminish glacial volume and capacity to store water,thus jeopardizing the sustainability of water resources in the basin.

Square Logistic Model for the Appearance of Lethal Recessive Homozygous Genotype in Random Mating Population

From the random mating population of maize, the relationship between heterosis and albino seedling was analyzed by means of mathematical theory, further the square logistic model for the appearance of lethal recessive homozygous genotype was deduced. The model shows that heterosis can determine the genetic structure and proportion of population. It approves, that the proportion of aa in each generation of maize seedlings shows a similar Logistic curve in growth process till equilibrium, so long as Aa containins lethal gene a from mutation presents heterosis. The ratio of equilibrium state of aa is determined by the ratio of AA-Aa fitness. Heterosis is helpful for the keeping of genetic diversity of population.

Drug Sensitive Test on Main Pathogenic Bacteria of Cow Recessiveness Mastitis Using Traditional Chinese Medicine Preparation “Zengrujianniusan”

According to the theory of Chinese veterinary medicine and characteristics of Chinese herbal medicine, four different preparations of compound Chinese medicine ＂Zengrujianniusan＂ were composed, and the prepared water decoction was used to carry on the bacteriostatic test on main pathogens of cow recessiveness mastitis. The results showed that the four different prescriptions of water decoction all had antibacterial effects. The prescription 3 was sensitive to Staphylococcus aureus and Streptococcus agalactiae, while the other three prescriptions showed high sensitivity, and the prescription 3 had the strongest bacteriostatic effects.

The Investigation of Main Pathogens Causing Dairy Cattle Recessive Mastitis in Eastern Hebei

[Objective]This paper aimed to determine the main pathogens causing dairy cattle recessive mastitis in eastern Hebei and provide certain reference for local veterinarians and cow farmers to prevent and cure the disease.[Method]512 cows from 5 different farms in eastern Hebei were selected,and LMT,milk ph test and somatic cell direct counting methods were combined and used to conduct recessive mastitis＇ s epidemiological investigation,as well as isolate and identify the pethogens.[Result]The results indicated that the incidence of recessive mastitis is 60.7%（311 / 512）,bacteria isolation rate reached 87.8%（273 /311）.Total 81 isolates,belonging to 3 classes and 5 types were identified in milk samples of positive milk area from 273 cows with recessive mastitis.Among which,19 isolates were Streptococcus,accounting for 23.45%.Staphylococcus had 31 isolates,accounting for 38.27%.Enterobacter had 3,accounting for 3.7%.Other unshaped had 28 isolates,accounting for 34.6%.[Conclusion] The main pathogens caused dairy cattle recessive mastitis in eastern Hebei were Streptococcus agalactiae and Staphylococcus aureus.

Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western analysis.RESULTSThis study demonstrates that： （1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

Utilization of eui Gene from a Recessive Tall Rice Mutant 02428h in Breeding

In order to improve the panicle extrusion of photo- and thermo-sensitive sterile line ‘Pei＇ai 64S＇ by using elongated uppermost internode （eul） gene of the wide compatibility rice mutant ‘02428h＇, a new photo- and thermo-sensitive sterile line ‘P8hS＇ characterized with elongated uppermost internode was developed by transferring the eui gene into Pei＇ai 64S through three successive backcrossing, Compared with Pei＇ai 64S, the plant height of P8hS was 35.6 cm higher resulted from the elongation of the uppermost and the second internodes from the top. The panicle extrusion of Pei＇ai 64S was completely improved and positive effects were found on the main economic characters of P8hS and its hybrids by introducing euigene into Pei＇ai 64S.

The impact of earlier flood recession on metacommunity diversity of wintering waterbirds at shallow lakes in the middle and lower Yangtze River floodplain

The hydrological regime in wetlands plays an important role in the process of wintering waterbird metacommunity assemblage.However,increasing frequency of extreme climate and the intensification of human activities,such as the construction of sluices and dams,have resulted in frequently abnormal hydrological regime in the middle and lower Yangtze River floodplain.In recent years,earlier flood recession has become one of the main hydrological problems faced in the shallow lakes,having a great impact on wetland biodiversity.It is necessary to understand the impact of earlier flood recession on waterbirds,an indicator of wetland biodiversity,and the metacommunity concept is helpful to elucidate the underlying mechanism involved in the processes of assemblage by waterbird communities.In this study,we surveyed the wintering waterbirds at three sub-lakes of Caizi Lakes during 2019-2020 and 2020-2021 and compared the richness,abundance,alpha and beta diversity of waterbirds in and among local metacommunities under earlier flood recession and normal hydrological regime.The results showed that the earlier flood recession reduced the species richness in the early stage and abundance in the late stage,it also reduced the Shannon-Wiener index in the early stage and increased the dissimilarity between and within waterbird metacommunities in the late stage.The partition of beta diversity showed that the turnover component played a major role in the process of waterbird metacommunity assemblage.It was found that the earlier flood recession reduced the richness,abundance in different stages of flood recession,which also increased the turnover of waterbirds.Metacommunities with high habitat heterogeneity had better resistance to abnormal hydrological regime,which resulted in high dissimilarity between and within metacommunities.The results of this study provide important information for waterbird conservation and water level management at shallow lakes in the middle and lower Yangtze River floodplain.

The Major Recessive Calamities Affecting the Wheat Production in Chuxiong Prefecture and Control Countermeasures

The impact of recessive calamities was analyzed,including seasonal drought,cold injury,dry hot wind and aphid in the wheat production of Chuxiong Prefecture,and the countermeasures that prevented and controlled the recessive calamities in a target-oriented way were proposed,including the improvement of basic farmland,the application of organic manure,the promotion of the breed with high stress resistance,the seedling at suitable date,the improvement of control on fertilizing and watering,the enhancement of management on cultivating and controlling disease in time,and the breeding new variety adaptive to local ecosystem,in order to advance the wheat production in a sustainable way.

Autosomal recessive hereditary auditory neuropathy

Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. Autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without evidence of peripheral neuropathy at the time of this writing. Conclusions: In this study, patients with feature of non- syndromic hereditary auditory neuropathy were identified in three Chinese families.Pedigree analysis indicates autosomal recessive inheritances in the pedigrees. The observed inheritance and clinical audiologic findings are different from those previously described for non-syndromic low-frequency sensorineural hearing loss. This information should facilitate future molecular candidate genes screening for understanding the mechanism of AN.

Hypocalcified autosomal recessive amelogenesis imperfecta—A case report

Amelogenesis imperfecta is an unusual hereditory disorder affecting both primary and permanent dentition. We present a rare case of hypocalcified auto-somal recessive amelogenesis imperfecta occuring in primary dentition in a 7-year-old girl with a family history of consanguineous marriage. Clinical and radiological examination revealed discoloration and hypoplasia of enamel with easy chipping affecting both maxillary and mandibular dentition.

Investigation of Four Genes Responsible for Autosomal Recessive Congenital Cataract and Highly Expressed in the Brain in Four Unrelated Tunisian Families

Purpose: To identify the causative gene for phenotypes associating autosomal recessive congenital cataract, mental retardation and congenital cataract, mental retardation and microcephaly in four unrelated Tunisian families. Methods: Four genes (EPHA2, GALK1, GCNT2, and CRYBB1) were selected based on expression in human brain and their known or putative function. Linkage analyses were performed for the four genes in multiple affected and unaffected families’ members and results were explored by the GeneMapper ID v3.2 software. Results: No linkage was identified for the four studied genes in the four families. Affected members of each family did not share common haplotypes in corresponding candidate regions containing selected gene. Conclusion: Although the four studied genes were reported responsible for autosomal recessive congenital cataract and highly expressed in the human brain, we report no linkage for EPHA2, GALK1, GCNT2, and CRYBB1 genes in four families with congenital cataract, mental retardation and congenital cataract, mental retardation and microcephaly.

Molecular diagnosis of autosomal recessive cerebellar ataxia in the whole exome/genome sequencing era

Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.

THE THREE FLAVOURINGS IN THE SEX-LINKED RECESSIVE LETHAL TEST OF DROSOPHILA MELANOGASTER

Since Cinnamomum japonicum,Illicium verum and Zanthoxylumbungeanum are People’s favourites,it seems to be necessary toevaluate their safety accurately.Wild-type Oregon K strainof Drosophila melanogaster and Mutant stock of Base（Muller-5）were used in the test.From F2 generation the mutagenicity hadbeen detected in three stages of germ-cell development by sex-linked recessive lethal test of Drosophila in negative control,

Novel Pathogenic Mutation of PNPLA1 Identified in Autosomal Recessive Congenital Ichthyosis:A Case Report

Autosomal recessive congenital ichthyosis(ARCI)is characterized by being born as collodion babies,hyperkeratosis,and skin scaling.We described a collodion baby at birth with mild ectropion,eclabium,and syndactyly.Whole exome sequencing showed a compound heterozygous variant c.[56C>A],p.(Ser19X)and c.[100G>A],p.(Ala34Thr)in the PNPLA1 gene[NM_001145717;exon 1].The protein encoded by PNPLA1 acts as a unique transacylase that specifically transfers linoleic acid from triglyceride toω-hydroxy fatty acid in ceramide,thus giving rise toω-O-acylceramide,a particular class of sphingolipids that is essential for skin barrier function.The variant was located in the patatin core domain of PNPLA1 and resulted in a truncated protein which could disrupt the function of the protein.This case report highlights a novel compound heterozygous mutation in PNPLA1 identified in a Chinese child.

Autosomal recessive spinocerebellar ataxia type 4 with a VPS13D mutation:A case report

BACKGROUND Autosomal recessive spinocerebellar ataxia type 4(SCAR4)is a type of SCA that is a group of hereditary diseases characterized by gait ataxia.The main clinical features of SCAR4 are progressive cerebellar ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.To date,many gene dysfunctions have been reported to be associated with SCAR4.CASE SUMMARY Here,we report a novel compound heterozygous mutation,c.3288delA(p.Asp1097-ThrfsTer6),in the VPS13D gene in a young female Chinese patient.The patient found something wrong with her legs about 10 years ago and presented with the typical characteristics of SCAR4 when she came to the hospital,including ataxia,neuropathy,and positive pyramidal signs.She was then diagnosed with SCAR4 and went home with symptomatic schemes.CONCLUSION SCAR4 is a hereditary disease characterized by ataxia,pyramidal signs,neuropathy,and macrosaccadic intrusions.We report a novel compound heterozygous mutation,c.3288delA(p.Asp1097ThrfsTer6),in the VPS13D gene,which enriches the gene mutation spectrum and provides additional information about SCAR4.

X-linked recessive Kallmann syndrome:A case report

BACKGROUND Kallmann syndrome(KS),also known as hypogonadotropic hypogonadism(HH)or olfactory-gonadal dysplasia,is a genetic condition in which the primary symptom is a failure to begin puberty or a failure to fully complete it.It occurs in both males and females and has the additional symptoms of hypogonadism and almost invariably infertility.The condition has a low prevalence that is estimated to be 1 in 4000 for male HH cases overall and 1:50000 for KS.It is three to five times more common in males than females.Whether this is a true sex imbalance or a reflection of how difficult KS/HH is to diagnose correctly in males vs females has yet to be fully established.CASE SUMMARY This article reports a 26-year-old male presenting with delayed puberty.The synthetic decapeptide luteinizing hormone-releasing hormone stimulation test showed that the secretion levels of follicle-stimulating hormone and luteinizing hormone were delayed.The eigengenes commonly associated with idiopathic HH(IHH)were screened,and an X-linked recessive(KAL-1)mutation was found.His gonadotropin and testosterone levels increased significantly after pulsatile gonadotropin-releasing hormone(GnRH)subcutaneous therapy by pump.A relevant literature review on the recent advances in the diagnosis and treatment of KS and genetic counseling was conducted.CONCLUSION KS is caused by a KAL-1 mutation that follows an X-linked recessive inheritance pattern.Pulsatile GnRH subcutaneous therapy by pump was effective in this patient.