Golden retrievers help identify a novel gene for a skin disorder

A skin disease, ichthyosis, presenting with similar clinical features in golden retriever dogs and humans shares a common genetic basis. The identification of the altered gene in dogs, not only identifies an eighth gene for an ichthyosis type in human called autosomal recessive congenital ichthyosis (ARCI), but also provides for the first time evidences for the involvement of its gene product in the cutaneous barrier. These findings are published online in Nature Genetics (15 January 2012).

This ichthyosis type, belonging to ARCI, results in generalized scaling of the skin and is diagnosed at birth. While the disease is rare in humans, it is very frequent in golden retriever dogs because of inbreeding and it has not been counter-selected.

Catherine André, head of the Canine Genetics team at the Institut de Génétique et Dévelopment de Rennes, and Judith Fischer, head of the Institute for Human Genetics at the University clinics of Freiburg, as well as Dr Eric Guaguere, veterinary dermatology specialist in Lommes, France, and their colleagues took advantage of the unique breeding history of dog populations to identify the genetic alteration(s) responsible for this skin disorder in golden retriever dogs. Authors identified a unique mutation in the PNPLA1 gene, perfectly segregating on a recessive transmission mode. They then analywed the corresponding human gene in a collection of affected individuals for which no molecular cause had previously been identified. They showed that six affected individuals belonging to two families carry distinct mutations both affecting the catalytic domain of the protein. Further experiments involving electron microscopy, immunolocalization by confocal microscopy and biochemistry analyses allowed to precise the role of the protein. PNPLA1 lipase is located in between the upper epidermal and the lower layers of the cornified layer, and is required for the correct keratinocyte differentiation. It belongs to a family of proteins, PNPLA1 to PNPLA5, that are key elements in the lipid metabolism of the cutaneous barrier.

The study performed in dogs was supported by CNRS and the European Commission (FP7-LUPA, GA201370), thanks to the excellent LUPA coordinators Anne-Sophie Lequarré and Marilou Ramos-Pamplona. The Canine Genetics team continues to collect blood and skin biopsies in all other canine ichthyoses in any breed.

For further information, please visit

Dr Catherine André
Equipe Génétique du chien
Institut de Génétique et Développement de Rennes IGDR
UMR 6061 CNRS/Université de Rennes 1
2, Av. Léon Bernard
35043 Rennes cedex

Prepared by: CAndré

Canine epilepsy gene identified

A study led by LUPA Finnish scientist Hannes Lohi (inset), in collaboration with research groups from Sweden and Switzerland, has identified a mutation in a novel gene as the cause of a genetic-idiopathic epilepsy syndrome in the Lagotto Romagnolo dog breed. In a recent publication in PLoS Genetics, an epilepsy-associated mutation in LGI2 was shown to prevent the protein’s secretion which can result in a destabilized neural network that is prone to seizures. LGI2, like its homolog the human epilepsy gene LGI1, was demonstrated to encode a secreted protein that interacts with known neurological receptors. However, unlike LGI1, LGI2 is predominantly expressed during the immediate post natal period implying that its function may be more important during the neural network construction phase.
Epileptic seizures constitute one of the most common neurological disorders in both dogs and children. Given its various complex pathologies, it has been difficult to elucidate the genetic and molecular basis of the disease. As the disorder is enriched in several isolated canine breeds, the dog with its more homogenous genetic architecture presents as a good model to study and understand familial epilepsies.In the Lagotto breed, a curly-haired dog initially selected for game water retrieval and truffle hunting traits, the epileptic disorder investigated is characterized by an onset at seven weeks and a highly predictable remission at four months. The LGI2 gene represents the first identified gene for focal epilepsy and a DNA test for the Lagotto breed is now commercially available through Genoscoper Oy (Ltd).

Two of the most common forms  of children’s epilepsy, Rolandic Epilepsy and Panayiotopoulous Syndrome, are known to occur during the 2-10 year age period which is the equivalent age range of the Lagotto epilepsy manifestation. Both canine and human disorders present similar pathologies. Thus, LGI2 may likewise be considered as a candidate gene for some forms of human juvenile epilepsy.

Complete details of this study are available from the open access journal PLoS Genetics. This work is highlighted on Cordis News (press released prepared by the European Commission) and in the open journal Disease Models and Mechanisms.

A mutation causing wrinkled skin of Shar-Pei dogs is linked to periodic fever disorder

An international investigation has uncovered the genetics of the Shar-Pei dog’s characteristic wrinkled skin. The researchers, led by scientists at Uppsala University and the Broad Institute, have connected this mutation to a periodic fever disorder and they propose that the findings could have important human health implications. Details appear on March 17 in the open-access journal PLoS Genetics.

Purebred dogs are selected for defined physical features, and the inadvertent enrichment for disease-risk genes may have unexpected health consequences. The thickened and wrinkled skin of Shar-Pei dogs contains an excess of hyaluronan, most likely due to the over-activation of the hyaluronan synthase 2 (HAS2) gene. The Shar-Pei also has a high prevalence of a periodic fever disorder similar to human inherited autoinflamatory periodic fever syndromes. Hyaluronan may create a ‘danger’ signal to the immune system, analogous to the effects a pathogen may have. Because of health implications, Shar-Pei breed clubs have strongly supported research into the cause of periodic fever.

To find the genetic cause for wrinkled skin, the researchers first compared the Shar-Pei genome to that of other dog breeds. Simultaneously, they compared the genome of healthy and sick Shar-Pei to locate the mutation for the fever. Both studies pinpointed the same region, which contained the HAS2 gene. In this breed alone, a DNA segment located close to HAS2 was duplicated erroneously, sometimes multiple times.

“It was really exciting to realize that the two traits had the same genetic origin,” says Mia Olsson (in picture), one of the authors. “Copies of the duplicates segment increase the risk for periodic fever in these dogs, and the overproductin of hyaluronan is the predisposing factor.”

“With this genetic information, people can avoid breeding Shar-Pei with many duplications,” said study co-author Linda Tintle. “Understanding the causes will also lead to more effective treatments.”

The researchers have shed light on the role of hyaluronan in inflammatory disease. The association of HAS2 dysregulation and autoinflammation is of wide interest since the genetic cause of periodic fever syndromes in approximately 60% of human cases remains unexplained. “The finding that hyaluronan is a major trigger of fever opens a new research field in canine and human inflammatory disease,” said senior author Kerstin Lindblad-Toh.

SOURCE: Public Library of Science

This study is also featured in the following: Science NOW; U.S. News and World Report; LiveScience; Cosmos and Eureka! Science News.

A Bobtail helps solve a rare respiratory disease !!

Researchers from the LUPA Consortium have discovered a new gene responsible for the development of a human respiratory disease thanks to the study of the same illness naturally occurring in pet dogs.  Primary ciliary dyskinesis (PCD) is a rare genetic disease affecting one human out 20.000 and characterized by abnormally functioning cellular cilia. Cilia are very abundant at the surface of respiratory airways, when beating they allow the elimination of microorganisms from air. If cilia are immotile or not motile enough affected people develop frequent respiratory infections leading to a progressive loss of lung functions. Mutations in about ten different genes can be responsible for this condition but more than 60% of cases are still unsolved. Animals may develop the same disease.

In 2007 a few Old English Sheepdogs suffering from chronicle bronchitis were examined at the Veterinary Faculty of the University of Liège. The frequency of affected dogs among pedigrees suggests a genetic disease. Moreover one dog presented a situs inversus, an inversion of the heart position. Together with respiratory troubles PCD can lead to organs displacement due to dysfunction of specific motile cilia during embryonic development. The analysis of the genetic material from 5 affected and 15 healthy Old English Sheepdogs led to the discovery of a region on chromosome 34 associated with the development of the disease. Among the 151 genes included in the region ten were coding for proteins involved in cilia function. All the exons were sequenced and a disrupting mutation was discovered in CCDC39 coding for a protein with not yet known function regarding cilia structure and motility.As this gene was not implied in human PCD cases fifty samples from people harbouring similar cilia defects as dogs were screened for mutations in CCDC39. Fifteen different mutations were identified explaining about 5% of all human PCD cases. This study brightly illustrates the ability of the dog model to solve the genetic basis of similar human diseases, the goal pursued by the European project LUPA. The discovery of the implication of CCDC39 in PCD cases will help the genetic counselling of affected families. Regarding dogs a genetic test has been developed to detect Old English sheepdog carriers of the mutation to prevent breeding carriers and giving birth to potentially affected puppies.

A complex immune disease partly deciphered using dog

To find genes for human common complex diseases, thousands of blood samples are needed from both patients and healthy controls. The structure of dog breeds provided by selective breeding practices makes it much easier to find pathogenic genes with a smaller number of samples. This is the primary goal of the LUPA project and has elegantly been demonstrated recently by a group of Scandinavian and American scientists.

The Nova Scotia duck tolling retriever is often affected by an autoimmune disease where the dog develops joint complaints and inflammatory symptoms in various inner organs. Many of the clinical features are similar to the human Systemic Lupus Erythematosus (SLE). Among these, dogs affected frequently display antibodies against the nuclei of the body’s own cells and always showed arthritis. The Nova Scotia breed was decimated by canine distemper virus in the early 20th century. The dogs that survived may have been the dogs with the strongest immune system, and this strong immune response is now also resulting in an autoimmune disorder.  The researchers sifted through the DNA of 81 diseased dogs and 57 healthy dogs and identified five regions in the genome that each, greatly increase the risk of developing the disease. SLE in humans is caused by many genes and therefore scientists were not surprised to find several risk factors that contribute to the disease in dogs. It’s worth pointing out that the canine risk factors are very strong. The risk factors that have been found thus far in humans with SLE may double the risk, but in dogs, each disease gene increases the risk about five times. The scientists have examined what the genes are in the risk regions and note that several of them govern the activation of T cells, the white blood cells that deal with viruses in our immune system. The genes that have thus far been found in humans with SLE do not primarily regulate T cells, but a major share of the genetic risk factors is still unknown in humans. This study opens the door for further studies of specific T-cell activation pathways in human populations. Such studies might lead to better treatment options for human rheumatic diseases and SLE.

Original article:
M Wilbe et al. Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.
Nature Genetics, 2010. DOI : 10.1038/ng.525

Vulgarisation article:
Dogs May Provide an Excellent Model for Understanding Human Complex Diseases
ScienceDaily (Feb. 2, 2010)

How did the Shar-pei get its famous wrinkles?

Scientists at the University of Washington analyzed the genetics of 10 dog breeds to locate the most-differentiated regions of their genes. They identified 155 distinct locations in the animals’ genetic code that could play a role in giving breeds their distinctive appearances. The results show some conspicuous physical traits, or phenotypes, such as height and coat color, can be traced to particular genes of beagles, border collies, dachshunds, poodles, among others. To characterize candidate genes in more detail, they focused on a region on chromosome 13 with evidence of selection in the Shar-Pei and containing three genes (SNTB1, FTSJ1, and HAS2). A distinguishing characteristic of the Shar-Pei is cutaneous mucinosis, or excessive skin wrinkling. The degree of skin folds correlates with high mucin content and elevated levels of hyaluronic acid. HAS2 codes for the hyaluronic acid synthase, the enzyme responsible for the production of the hyaluronic acid. To test the hypothesis that genetic variation in HAS2 contributes to skin wrinkling, they studied 32 wrinkled and 18 smooth-coated Shar-peis and found four small, but significant, differences in the HAS2 gene of the two skin types of the Shar-pei versus the other breeds. Rare mutations in human HAS2 gene have been described that lead to really severe wrinkling in humans, too. As well as giving insights into the Shar-pei, the research has also identified a raft of other locations in the dog genome that can now be investigated further to understand better why pedigree animals look the way they do.

Original article:
Akey JM et al. Tracking footprints of artificial selection in the dog genome.
Proc Natl Acad Sci U S A. 2010. 107(3):1160-5.

Summarized from the article of Jonathan Amos.
BBC News

Short legs breeds genetically solved

American scientists have discovered why some dog breeds have very short legs. In fact breeds as dachshunds, corgis or basset hounds have an extra copy of a normal gene to thank for their diminutive stature. Dogs come in a wide variety of body shapes and sizes and researchers focused on eight breeds known to have chondrodysplasia — short legs relative to body size with curved and heavier-bones than normal and compared their genomes to the ones from breeds not harboring that trait. They pinpointed an extra stretch of DNA on chromosome 18 in each dog from short-legged breeds, but in none of 204 control dogs examined. This extra stretch of DNA turned out to have a sequence almost identical to another gene important for limb development, called FGF4. Located at the opposite end of chromosome 18 in dogs, the original FGF4 gene was duplicated at some point in the dog lineage, creating a new copy elsewhere called the fgf4 retrogene. In rare cases, messenger RNA — molecules made from DNA that carry information to cellular machinery, which then makes proteins—can get turned back into DNA. If this DNA then gets plopped back into the genome in a new neighborhood, and conditions are right for this genetic new kid on the block to become active, the extra DNA becomes a retrogene. Most pieces of DNA that hop around the genome are not functional, in part because they may land in inhospitable places in the genome. But this retrogene landed in a sweet spot that allowed it to change dog leg length. This retrogene is a dominant allele, meaning that only one copy is needed for chondrodysplasia to appear. As none of the wolves tested had this retrogene, this gene duplication probably happened after dogs first domestication and before division of early dogs into modern breeds so anywhere between 300 and 15,000 years ago.

Summarized from the article of Laura Sanders: Retrogene causes short legs in man’s best friends
Sciencenews. August, 2009. Vol.176 #4 (p.8)

Original scientific article: Parker HG et al. An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 2009. 325:995-8.

A new gene for brittle bone disease

Osteogenesis imperfecta also known as brittle bone disease is a human genetic bone disorder affecting 6 to 7 per 100,000 people worldwide and characterized by extremely fragile bones and teeth. Most cases are caused by mutations in two genes encoding different subunits of the collagen type I molecule. Several hundred mutations in these two genes have been described, most as dominant forms. The maturation and the correct folding of collagens is complicated and involves a large number of accessory proteins. Recently mutations in two of these proteins were found in patients with recessive forms. This disease also occurs in dogs, it has been described in Golden Retrievers, Beagles, Collies, Poodles, Norwegian Elkhounds, and Bedlington Terriers. In Golden Retrievers and Beagles mutations in the two genes implied in the synthesis of collagen type I have also been discovered, for other canine cases the underlying genetic defect has not yet been elucidated. Here several rough-coated Dachshunds showed a similar disease inherited as a monogenic autosomal recessive trait. Among DNA segments perfectly shared by the five affected dogs there was the SERPINH1 gene known to be involved in collagen maturation. The sequence of this gene in healthy and affected Dachshunds showed a single mutation exclusively shared by all affected dogs but not by healthy controls. So this mutation is most likely responsible for the disease. The knowledge of this mutation enables genetic testing and will allow breeders to eradicate the deleterious allele from the Dachshund population. SERPINH1 mutations might also be responsible for some human forms, where the causative mutation has not yet been identified.

Original article:
Drögemüller C et al. A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta. PLoS Genet. 2009 5(7):e1000579.

A clue for hairless dog!

Mexican hairless dog were sacred by the Aztecs and there are statues of them dating back 3700, hairless dogs were also described in Ancient Egypt. Scientists using nowadays hairless dogs have discovered the mutated gene responsible for this strange appearance. Hairless dogs not only have a hair coat sparse or absent but also missing or abnormally shaped teeth. The inheritance of this phenotype is a monogenic semi-dominant trait meaning that heterozygous dogs are hairless but homozygous mutant die during embryogenesis.

By genotyping only 20 hairless and 19 coated Chinese Crested dogs with the 50K canine Affymetrix v2 array, the mutation was mapped to the canine chromosome 17 in a region of 1.7 Mb. Fine mapping with a larger set of Chinese dogs along with Mexican and Peruvian hairless dogs reduced the associated region to a 102 Kb interval containing two genes including one truncated pseudogene. The other gene was similar to the FOX transcription factor family, important regulators of development, and showed the highest similarity with FOXI3 gene. In mice this gene is expressed in the epithelium of the hair and whisker placodes and developing teeth. Sequencing analysis of the FOXI3 gene in all hairless dogs revealed a 7-bp duplication in the exon 1 that produces a frameshift and a premature Stop codon. So the most likely explanation for this phenotype is a haplo-insufficiency of the FOXI3 protein whereas a complete lack of the protein will cause embryonic lethality. This study in dog genetics is giving new insight into general developmental biology.

Reference: “a mutation in hairless dogs implicates FOXI3 in ectodermal development” Drögemüller C, Karlsson EK, Hytönen MK, Perloski M, Dolf G, Sainio K, Lohi H, Lindblad-Toh K, Leeb T. Science. 2008 Sep 12;321 (5895) 1462.

PMID: 18787161 [PubMed – Indexed forMEDLINE]