<i>TBX6</i>Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

Wu, N.; Xuan, Ming; Xiao, Jianqiu; Z, Wu; Chen, X; Shinawi, Marwan; Shen, Ya; Yu, Guangrong; Liu, Jing; Xie, Hua; Zs, Gucev; S, Liu; Yang, Nan; Al-Kateb, Hussam; Chen, J; Zhang, Jingwan; Hauser, Natalie; Zhang, T; Tasić, Ljubica; P, Liu; X, Su; X, Pan; C, Liu; Wang, L; Shen, Jianxiong; Chen, Y; Choy, Kwong Wai; Wang, J; Wang, Q; S, Li; Zhou, Weichen; Guo, J.; Wang, Y; Zhang, C; Zhao, Hong; An, Youzhong; Zhao, Yanyang; Z, Liu; Zuo, Yu; Tian, Ye; Weng, Xisheng; Vr, Sutton; Wang, H; Ming, Yue; Kulkarni, Shashikant; Tp, Zhong; Giampietro, P F; Dunwoodie, Sally L.; Cheung, SW; Zhang, X; Jin, Ling; Lupski,; Qiu, Guixing; Zhang, F

doi:10.1056/nejmoa1406829

Cited by 250 publications

(380 citation statements)

References 45 publications

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“…31 Interestingly, all five MMAF-affected subjects in Figures 1 and S3 had at least one loss-of-function mutation in CFAP43, CFAP44, or CFAP65, which is consistent with compound inheritance. 31 CFAPs are conserved in many ciliated organisms. The orthologs in C. reinhardtii are the flagella-associated proteins (FAPs), whose expression is strongly induced during flagellar regeneration.…”

Section: Semen Parameterssupporting

confidence: 54%

“…Some experimental details of the array-based CGH (aCGH) assay have been previously described. 30,31 The test DNA of each subject and the human male reference DNA (Promega) were fragmented by both AluI and RsaI digestion. DNA was labeled with the Agilent SureTag DNA Labeling Kit.…”

Section: Array-based Cghmentioning

confidence: 99%

“…Previously, we identified a common TBX6 hypomorphic allele in which homozygosity did not result in disease in human populations. 31 Rather, the compound inheritance of the hypomorphic allele plus a loss-of-function mutation led to congenital scoliosis. 31 Interestingly, all five MMAF-affected subjects in Figures 1 and S3 had at least one loss-of-function mutation in CFAP43, CFAP44, or CFAP65, which is consistent with compound inheritance.…”

Section: Semen Parametersmentioning

confidence: 99%

“…31 Rather, the compound inheritance of the hypomorphic allele plus a loss-of-function mutation led to congenital scoliosis. 31 Interestingly, all five MMAF-affected subjects in Figures 1 and S3 had at least one loss-of-function mutation in CFAP43, CFAP44, or CFAP65, which is consistent with compound inheritance. 31 CFAPs are conserved in many ciliated organisms.…”

Section: Semen Parametersmentioning

confidence: 99%

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Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

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Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

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Section: Semen Parameterssupporting

confidence: 54%

Section: Array-based Cghmentioning

confidence: 99%

Section: Semen Parametersmentioning

confidence: 99%

Section: Semen Parametersmentioning

confidence: 99%

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Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

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242

212

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“…These findings indicate that the Mesp2 +/− , Hes7 +/− , and Dll1 +/− mice do not have any similarities to the HVF mouse model, which develops autosomal dominant kyphoscoliosis with high penetrance without any requirement for environmental challenge such as hypoxia. Null mutations of Tbx6 , a key regulator of the Notch signaling pathway, cause congenital scoliosis in humans and rats 27, 52, 53, 54. However, the vertebral defects may occur in the cervical, thoracic, or lumber spine, in contrast to Hvf mice, in which the defects occurred only in L 2 to L 5 vertebrae.…”

Section: Discussionmentioning

confidence: 99%

An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

et al. 2018

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Kyphosis and scoliosis are common spinal disorders that occur as part of complex syndromes or as nonsyndromic, idiopathic diseases. Familial and twin studies implicate genetic involvement, although the causative genes for idiopathic kyphoscoliosis remain to be identified. To facilitate these studies, we investigated progeny of mice treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) and assessed them for morphological and radiographic abnormalities. This identified a mouse with kyphoscoliosis due to fused lumbar vertebrae, which was inherited as an autosomal dominant trait; the phenotype was designated as hereditary vertebral fusion (HVF) and the locus as Hvf. Micro–computed tomography (μCT) analysis confirmed the occurrence of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae in HVF mice, consistent with a pattern of blocked vertebrae due to failure of segmentation. μCT scans also showed the lumbar vertebral column of HVF mice to have generalized disc narrowing, displacement with compression of the neural spine, and distorted transverse processes. Histology of lumbar vertebrae revealed HVF mice to have irregularly shaped vertebral bodies and displacement of intervertebral discs and ossification centers. Genetic mapping using a panel of single nucleotide polymorphic (SNP) loci arranged in chromosome sets and DNA samples from 23 HVF (eight males and 15 females) mice, localized Hvf to chromosome 4A3 and within a 5‐megabase (Mb) region containing nine protein coding genes, two processed transcripts, three microRNAs, five small nuclear RNAs, three large intergenic noncoding RNAs, and 24 pseudogenes. However, genome sequence analysis in this interval did not identify any abnormalities in the coding exons, or exon‐intron boundaries of any of these genes. Thus, our studies have established a mouse model for a monogenic form of nonsyndromic kyphoscoliosis due to fusion of lumbar vertebrae, and further identification of the underlying genetic defect will help elucidate the molecular mechanisms involved in kyphoscoliosis. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research

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Cognitive Phenotypes and Genomic Copy Number Variations

Lupski

2015

JAMA

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In this issue of JAMA, Männik and colleagues 1 report that large (>250 kilobase [kb] pairs) structural variants in the genome, specifically deletion and duplication copy number variations (CNVs), were associated with cognitive phenotypes including intellectual disability and reduced educational achievement. These CNVs are deletions and duplications of DNA sequences in the human genome that can be considered as deviations from the normal diploid state at a given location in the genome and represent differing numbers of copies of genetic sequences. The authors also identified and examined the phenotypic consequences of genomic structural variation associated with known genomic disorders 2 among individuals in whom the genomic disorders were not initially clinically recognized.Männik et al initially studied a large Estonian general population, using a random sample cohort of approximately 8000 from the 52 000 DNA samples available in the wellestablished Estonian Genome Center biobank that contains 5% of the adult Estonian population. Importantly, the study participants who were enrolled in the biobank had phenotype information available for study. They were each examined by a general practitioner who completed health-and lifestyle-related questionnaires, and reported clinical diagnoses. Public educational history also was available for analyses.The investigators used genome-wide assays to identify CNVs to determine the medical burden of rare CNVs in the general population. Such genomic assays have been clinically available in Europe and the United States for a decade, often replacing chromosomal analysis, particularly in children manifesting developmental delay. 3 Clinical cytogenetic chromosome studies can identify changes in chromosome number (eg, trisomy 21 associated with Down syndrome) and even some chromosomal microdeletions and microduplications greater than 5 to 10 million base (Mb) pairs in size. However, the new genomic assays used in this study can detect submicroscopic genomic changes including CNVs. Thus, many more genomic changes of potential medical relevance can now be robustly identified using these genome-wide assays.

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TBX6Null Variants and a Common Hypomorphic Allele in Congenital Scoliosis

Cited by 250 publications

References 45 publications

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

An N‐Ethyl‐N‐Nitrosourea (ENU) Mutagenized Mouse Model for Autosomal Dominant Nonsyndromic Kyphoscoliosis Due to Vertebral Fusion

Cognitive Phenotypes and Genomic Copy Number Variations

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