LINE-1 Mediated Insertion into Poc1a (Protein of Centriole 1 A) Causes Growth Insufficiency and Male Infertility in Mice.

Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.

The Histone Methyltransferase Gene Absent, Small, or Homeotic Discs-1 Like Is Required for Normal Hox Gene Expression and Fertility in Mice.

Chromatin remodeling influences gene expression in developing and adult organisms. Active and repressive marks of histone methylation dictate the embryonic expression boundaries of developmentally regulated genes, including the Hox gene cluster. Drosophila ash1 (absent, small or homeotic discs 1) gene encodes a histone methyltransferase essential for regulation of Hox gene expression that interacts genetically with other members of the trithorax group (TrxG). While mammalian members of the mixed lineage leukemia (Mll) family of TrxG genes have roles in regulation of Hox gene expression, little is known about the expression and function of the mammalian ortholog of the Drosophila ash1 gene, Ash1-like (Ash1l). Here we report the expression of mouse Ash1l gene in specific structures within various organs and provide evidence that reduced Ash1l expression has tissue-specific effects on mammalian development and adult homeostasis. Mutants exhibit partially penetrant postnatal lethality and failure to thrive. Surviving mutants have growth insufficiency, skeletal transformations, and infertility associated with developmental defects in both male and female reproductive organs. Specifically, expression of Hoxa11 and Hoxd10 are altered in the epididymis of Ash1l mutant males and Hoxa10 is reduced in the uterus of Ash1l mutant females. In summary, we show that the histone methyltransferase Ash1l is important for the development and function of several tissues and for proper expression of homeotic genes in mammals.

Advances in Skeletal Dysplasia Genetics.

Skeletal dysplasias result from disruptions in normal skeletal growth and development and are a major contributor to severe short stature. They occur in approximately 1/5,000 births, and some are lethal. Since the most recent publication of the Nosology and Classification of Genetic Skeletal Disorders, genetic causes of 56 skeletal disorders have been uncovered. This remarkable rate of discovery is largely due to the expanded use of high-throughput genomic technologies. In this review, we discuss these recent discoveries and our understanding of the molecular mechanisms behind these skeletal dysplasia phenotypes. We also cover potential therapies, unusual genetic mechanisms, and novel skeletal syndromes both with and without known genetic causes. The acceleration of skeletal dysplasia genetics is truly spectacular, and these advances hold great promise for diagnostics, risk prediction, and therapeutic design.

A novel loss-of-function mutation in Npr2 clarifies primary role in female reproduction and reveals a potential therapy for acromesomelic dysplasia, Maroteaux type.

We discovered a new spontaneous mutant allele of Npr2 named peewee (pwe) that exhibits severe disproportionate dwarfism and female infertility. The pwe phenotype is caused by a four base-pair deletion in exon 3 that generates a premature stop codon at codon 313 (L313X). The Npr2(pwe/pwe) mouse is a model for the human skeletal dysplasia acromesomelic dysplasia, Maroteaux type (AMDM). We conducted a thorough analysis of the female reproductive tract and report that the primary cause of Npr2(pwe/pwe) female infertility is premature oocyte meiotic resumption, while the pituitary and uterus appear to be normal. Npr2 is expressed in chondrocytes and osteoblasts. We determined that the loss of Npr2 causes a reduction in the hypertrophic and proliferative zones of the growth plate, but mineralization of skeletal elements is normal. Mutant tibiae have increased levels of the activated form of ERK1/2, consistent with the idea that natriuretic peptide receptor type 2 (NPR2) signaling inhibits the activation of the MEK/ERK mitogen activated protein kinase pathway. Treatment of fetal tibiae explants with mitogen activated protein kinase 1 and 2 inhibitors U0126 and PD325901 rescues the Npr2(pwe/pwe) growth defect, providing a promising foundation for skeletal dysplasia therapeutics.