Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility (original) (raw)
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MNS1 variant associated with situs inversus and male infertility
European Journal of Human Genetics
Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode...
Carpenter syndrome is an autosomal-recessive multiple-congenital-malformation disorder characterized by multisuture craniosynosto- sis and polysyndactyly of the hands and feet; many other clinical features occur, and the most frequent include obesity, umbilical hernia, cryptorchidism, and congenital heart disease. Mutations of RAB23, encoding a small GTPase that regulates vesicular transport, are present in the majority of cases. Here, we describe a disorder caused by mutations in multiple epidermal-growth-factor-like-domains 8 (MEGF8), which exhibits substantial clinical overlap with Carpenter syndrome but is frequently associated with abnormal left-right patterning. We describe five affected individuals with similar dysmorphic facies, and three of them had either complete situs inversus, dextrocardia, or transposition of the great arteries; similar cardiac abnormalities were previously identified in a mouse mutant for the orthologous Megf8. The mutant alleles comprise one nonsense, three missense, and two splice-site mutations; we demonstrate in zebra- fish that, in contrast to the wild-type protein, the proteins containing all three missense alterations provide only weak rescue of an early gastrulation phenotype induced by Megf8 knockdown. We conclude that mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members. We did not observe any subject with biallelic loss-of function mutations, suggesting that some residual MEGF8 function might be necessary for survival and might influence the phenotypes observed.
MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates
Nature genetics, 2015
Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.
A human laterality disorder associated with a homozygous WDR16 deletion
European Journal of Human Genetics, 2014
The laterality in the embryo is determined by left-right asymmetric gene expression driven by the flow of extraembryonic fluid, which is maintained by the rotary movement of monocilia on the nodal cells. Defects manifest by abnormal formation and arrangement of visceral organs. The genetic etiology of defects not associated with primary ciliary dyskinesia is largely unknown. In this study, we investigated the cause of situs anomalies, including heterotaxy syndrome and situs inversus totalis, in a consanguineous family. Whole-exome analysis revealed a homozygous deleterious deletion in the WDR16 gene, which segregated with the phenotype. WDR16 protein was previously proposed to play a role in cilia-related signal transduction processes; the rat Wdr16 protein was shown to be confined to cilia-possessing tissues and severe hydrocephalus was observed in the wdr16 gene knockdown zebrafish. The phenotype associated with the homozygous deletion in our patients suggests a role for WDR16 in human laterality patterning. Exome analysis is a valuable tool for molecular investigation even in cases of large deletions.
Genetic architecture of laterality defects revealed by whole exome sequencing
European Journal of Human Genetics
Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1-two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.
Spectrum of Genetic Variants in a Cohort of 37 Laterality Defect Cases
Frontiers in Genetics
Laterality defects are defined by the perturbed left–right arrangement of organs in the body, occurring in a syndromal or isolated fashion. In humans, primary ciliary dyskinesia (PCD) is a frequent underlying condition of defective left–right patterning, where ciliary motility defects also result in reduced airway clearance, frequent respiratory infections, and infertility. Non-motile cilia dysfunction and dysfunction of non-ciliary genes can also result in disturbances of the left–right body axis. Despite long-lasting genetic research, identification of gene mutations responsible for left–right patterning has remained surprisingly low. Here, we used whole-exome sequencing with Copy Number Variation (CNV) analysis to delineate the underlying molecular cause in 35 mainly consanguineous families with laterality defects. We identified causative gene variants in 14 families with a majority of mutations detected in genes previously associated with PCD, including two small homozygous CNVs...
Two Populations of Node Monocilia Initiate Left-Right Asymmetry in the Mouse
Cell, 2003
positional information. Insight into upstream events that and Department of Genetics govern asymmetric gene expression has come from 2 Department of Internal Medicine study of mouse and human mutations affecting LR deand Department of Genetics velopment, which do not represent mutations in asym-3 Department of Pediatrics, Section of Cardiology metrically expressed genes. One of the best character-4 Department of Internal Medicine ized of these is the inversus viscerum (iv/iv) mouse Yale University School of Medicine (Hummel and Chapman, 1959). This mutation results in New Haven, Connecticut 06520 random development of LR asymmetry: 50% of liveborn iv/iv mice have normal orientation of the heart and viscera (situs solitus), the other 50% have a complete mirror Summary image reversal (situs inversus) (Layton, 1976). The expression of normally lateralized genes such as nodal, The vertebrate body plan has conserved handed leftlefty-2, and Pitx2 also becomes random: 25% of emright (LR) asymmetry that is manifested in the heart, bryos express nodal on the left, 25% on the right, 25% lungs, and gut. Leftward flow of extracellular fluid at bilaterally, and 25% do not express nodal in the lateral the node (nodal flow) is critical for normal LR axis plate mesoderm (Collignon et al., 1996; Lowe et al., determination in the mouse. Nodal flow is generated 1996). Iv is a point mutation in the left-right dynein (lrd) by motile node cell monocilia and requires the axogene, which encodes an outer arm axonemal (ciliary) nemal dynein, left-right dynein (lrd). In the absence of dynein (Supp et al., 1997). lrd, LR determination becomes random. The cation Kartagener syndrome is a human disease that results channel polycystin-2 is also required to establish LR in randomization of situs solitus and situs inversus (Afasymmetry. We show that lrd localizes to a centrally zelius, 1976), in addition to respiratory compromise and located subset of node monocilia, while polycystin-2 male infertility due to defective dynein function in the is found in all node monocilia. Asymmetric calcium tracheal cilia and in the sperm axoneme. At the molecusignaling appears at the left margin of the node coincilar level, Kartagener patients have defects in genes that dent with nodal flow. These observations suggest that encode several components of ciliary dynein (Olbrich et LR asymmetry is established by an entirely ciliary al., 2002; Bartoloni et al., 2002; Pennarun et al., 1999; mechanism: motile, lrd-containing monocilia generate Guichard et al., 2001). nodal flow, and nonmotile polycystin-2 containing cilia Targeted mutagenesis of two members of the heterosense nodal flow initiating an asymmetric calcium sigtrimeric kinesin family KIF3A (Marszalek et al., 1999; nal at the left border of the node. Takeda et al., 1999) and KIF3B (Nonaka et al., 1998) also result in ciliary defects, along with abnormal LR development, midgestation lethality, and multiple se
American journal of human genetics, 2018
Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, male infertility, and randomization of the left/right body axis as a result of defects of motile cilia and sperm flagella. We identified loss-of-function mutations in the open-reading frame C11orf70 in PCD individuals from five distinct families. Transmission electron microscopy analyses and high-resolution immunofluorescence microscopy demonstrate that loss-of-function mutations in C11orf70 cause immotility of respiratory cilia and sperm flagella, respectively, as a result of the loss of axonemal outer (ODAs) and inner dynein arms (IDAs), indicating that C11orf70 is involved in cytoplasmic assembly of dynein arms. Expression analyses of C11orf70 showed that C11orf70 is expressed in ciliated respiratory cells and that the expression of C11orf70 is upregulated during ciliogenesis, similar to other previously described cytoplasmic dynein-arm assembly factors. Furthermore, C11orf70 shows an interaction with cy...