Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome

The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders.     

Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch

The epidermis is a highly organized structure, the integrity of which is central to the protection of an organism. Development and subsequent maintenance of this tissue depends critically on the intricate balance between proliferation and differentiation of a resident stem cell population; however, the signals controlling the proliferation-differentiation switch in vivo remain elusive. Here, we show that mice carrying a homozygous missense mutation in interferon regulatory factor 6 (Irf6), the homolog of the gene mutated in the human congenital disorders Van der Woude syndrome and popliteal pterygium syndrome, have a hyperproliferative epidermis that fails to undergo terminal differentiation, resulting in soft tissue fusions. We further demonstrate that mice that are compound heterozygotes for mutations in Irf6 and the gene encoding the cell cycle regulator protein stratifin (Sfn; also known as 14-3-3sigma) show similar defects of keratinizing epithelia. Our results indicate that Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch and that Irf6 and Sfn interact genetically in this process.     

A common variant associated with prostate cancer in European and African populations

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.     

Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles

We identified constitutional truncating mutations of the BRCA1-interacting helicase BRIP1 in 9/1,212 individuals with breast cancer from BRCA1/BRCA2 mutation-negative families but in only 2/2,081 controls (P = 0.0030), and we estimate that BRIP1 mutations confer a relative risk of breast cancer of 2.0 (95% confidence interval = 1.2-3.2, P = 0.012). Biallelic BRIP1 mutations were recently shown to cause Fanconi anemia complementation group J. Thus, inactivating truncating mutations of BRIP1, similar to those in BRCA2, cause Fanconi anemia in biallelic carriers and confer susceptibility to breast cancer in monoallelic carriers.     

CXorf6 is a causative gene for hypospadias

46,XY disorders of sex development (DSD) refer to a wide range of abnormal genitalia, including hypospadias, which affects approximately 0.5% of male newborns. We identified three different nonsense mutations of CXorf6 in individuals with hypospadias and found that its mouse homolog was specifically expressed in fetal Sertoli and Leydig cells around the critical period for sex development. These data imply that CXorf6 is a causative gene for hypospadias.     

Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.     

X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations

Cornelia de Lange syndrome is a multisystem developmental disorder characterized by facial dysmorphisms, upper limb abnormalities, growth delay and cognitive retardation. Mutations in the NIPBL gene, a component of the cohesin complex, account for approximately half of the affected individuals. We report here that mutations in SMC1L1 (also known as SMC1), which encodes a different subunit of the cohesin complex, are responsible for CdLS in three male members of an affected family and in one sporadic case.