|NOTICIERO GENETICO SEGEHU Nº 6 - Octubre de 2007
La Sección de Genética Humana (SEGEHU) de la SAG ha decidido impulsar este Noticiero Genético para difundir novedades relacionadas a la práctica de la Genética Médica y Humana.
El mantenimiento y la difusión del mismo están a cargo de Martín Roubicek <firstname.lastname@example.org> y José E. Dipierri <email@example.com>
Se invita a todos los colegas a enviar sus contribuciones adjuntando un pequeño comentario de la novedad y el PDF o documento correspondiente. Agradecemos a los que han respondido a nuestra solicitud enviando material.
Se encuentran disponibles, a pedido de los interesados, los PDF de los articulos o documentos completos que se pueden solicitar a M Roubicek o JE Dipierri.
La genética de los altos y de los bajos.
El gen SHOX
La talla se encuentra determinada por muchos genes. Uno de estos genes es el short-stature homeoboxcontaining gene (SHOX), que codifica un factor de trascripción, el cual sería responsable del déficit de talla asociado al Síndrome de Turner. Las mutaciones de este gen son una de las causas genéticas más frecuentes de baja talla aislada o familiar. En la base www.shox.uni-hd.de se reportan mas de 50 mutaciones de este gen asociadas a múltiples cuadros que van desde baja talla “idiopática” a síndromes genéticos clínicamente reconocidos (Léri-Weill, Langer). El gen se caracteriza por su extrema variabilidad fenotípica y no existe información que permita distinguir los fenotipos sindrómicos de los no sindrómicos causados por la misma mutación. En el trabajo de Rappold et al. (2007) se determina el espectro fenotípico y molecular de la deficiencia del gen SHOX en un grupo numéricamente importante de personas y se desarrolla un "score" para seleccionar pacientes para estudios moleculares del gen SHOX. Si bien la talla promedio no era diferente entre los participantes con baja talla con o sin defectos del gen SHOX, éstos presentaban diferencias estadísticamente significativas respecto a algunas deformaciones óseas y signos dismórficos tales como antebrazo y miembros inferiores cortos, deformidad de Madelung, paladar alto e hipertrofia muscular. Se transcribe el score propuesto por los autores.
Scoring system for identifying patients that qualify for short-stature homeobox containing gene (SHOX) testing based on clinical criteria
Score item Criterion Score points
Arm span/height ratio (cociente brazada/talla) 96.5% 2
Sitting height/height ratio (talla sentado/total) 55.5% 2
Body–mass index (Indice Masa Corporal) P 50 4
Cubitus valgus Yes 2
Short forearm (antebrazo corto) Yes 3
Bowing of forearm (antebrazo incurvado) Yes 3
Appearance of muscular hypertrophy Yes 3
Dislocation of ulna (at elbow)(luxac.cúbito en codo)Yes 5
Genotypes and phenotypes in children with short stature: clinical indicators of SHOX haploinsufficiency.
Gudrun Rappold, Werner F Blum, Elena P Shavrikova, Brenda J Crowe, Ralph Roeth, Charmian A Quigley, Judith L Ross, Beate Niesler
Background: Short stature affects approximately 2% of children, representing one of the more frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions of the short stature homeobox-containing gene (SHOX) are found quite frequently in subjects with short stature. Haploinsufficiency of the SHOX gene causes short stature with highly variable clinical severity, ranging from isolated short stature without dysmorphic features to Le´ri-Weill syndrome, and with no functional copy of the SHOX gene, Langer syndrome.
Methods: To characterise the clinical and molecular spectrum of SHOX deficiency in childhood we assessed the association between genotype and phenotype in a large cohort of children of short stature from 14 countries.
Results: Screening of 1608 unrelated individuals with sporadic or familial short stature revealed SHOX mutations or deletions in 68 individuals (4.2%): complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). Although mean height standard deviation score (SDS) was not different between participants of short stature with or without identified SHOX gene defects (–2.6 vs –2.6), detailed examination revealed that certain bone deformities and dysmorphic signs, such as short forearm and lower leg, cubitus valgus, Madelung deformity, high-arched palate and muscular hypertrophy, differed markedly between participants with or without SHOX gene defects (p,0.001). Phenotypic data were also compared for 33 children with Turner syndrome in whom haploinsufficiency of SHOX is thought to be responsible for the height deficit.
Conclusion: A phenotype scoring system was developed that could assist in identifying the most appropriate subjects for SHOX testing. This study offers a detailed genotype-phenotype analysis in a large cohort of children of short stature, and provides quantitative clinical guidelines for testing of the SHOX gene.
Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany; firstname.lastname@example.org
J Med Genet 2007;44:306–313
El gen HMGA2
El trabajo de Weedon et al. (2007) demuestra que una única sustitución en el gen HMGA2 tiene influencia en la talla. Las personas homocigotas para esta variante son en promedio casi 1 cm más altos que los homocigotos para la versión corta del gen. Los heterocigotos presentan una talla intermedia entre ambos. Pese a que mutaciones raras y severas del gen HMGA2 pueden alterar el tamaño corporal en el ratón y en el hombre, se desconoce como el gen HMGA2 puede influir sobre la talla. La función de este gen es desenrollar la cromatina, por lo tanto Weedon et al. (2007) especulan que el gen podría influenciar la velocidad de replicación del ADN durante la división celular afectando de este modo el crecimiento corporal. Se adjuntan el trabajo original de Weedon et al., y un comentario de este trabajo en la revista Nature del 2 September 2007.
A common variant of HMGA2 is associated with adult and childhood height in the
Michael N Weedon1,2*, Guillaume Lettre3,4*, Rachel M Freathy1,2*, Cecilia M
Lindgren5,6*, Benjamin F Voight3,7, John R B Perry1,2, Katherine S Elliott5, Rachel
Hackett3, Candace Guiducci3 , Beverley Shields2, Eleftheria Zeggini5, Hana Lango1,2,
Valeriya Lyssenko8,9, Nicholas J Timpson5,10, Noel P Burtt3, Nigel W Rayner6, Richa
Saxena3,7,11, Kristin Ardlie3, Jonathan H Tobias12, Andrew R Ness13, Susan M Ring14,
Colin N A Palmer15, Andrew D Morris16, Leena Peltonen3, 17, 18, Veikko Salomaa19, The
Diabetes Genetics Initiative20, The Wellcome Trust Case Control Consortium21, George
Davey Smith10, Leif C Groop8,9, Andrew T Hattersley1,2, Mark I McCarthy5,6*, Joel N
Hirschhorn3,4,22*, Timothy M Frayling1,2*+
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic
variants influencing height, we examined genome-wide association data from 4921
individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were
associated with height (P=4x10-8). HMGA2 is also a strong biological candidate for
height because rare, severe mutations in this gene alter body size in mice and humans, so
we tested rs1042725 in additional samples. We confirmed the association in 19064 adults
from four further studies (P=3x10-11, overall P=4x10-16 including the genome-wide
association data). We also observed the association in children (P=1x10-6, N=6827) and a tall/short case-control study (P=4x10-6, N=3207). We estimate that rs1042725 explains ~0.3% of population variation in height (~0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitative traits; these results represent the first consistently replicated association with adult and childhood height.
Nature Genetics 39(10):1425-1250..
News: First 'tall gene' found. Genetic variant can add nearly a centimetre to your stature.
Nature, 2 September, 2007.
Published online: 2 September 2007; | doi:10.1038/news070827-8
First 'tall gene' found
Genetic variant can add nearly a centimetre to your stature.
Measuring up: height is influenced by hundreds of different genes.
A genetic survey of more than 34,000 people has revealed the first gene known to have a decisive effect on height in people of average stature. A change to just a single letter of genetic code is linked to a height boost of almost a centimetre in a healthy person, all other things being equal.
Although up to 90% of variation in people's height is thought to be down to genetics, identifying the genes involved is difficult because there are thought to be hundreds of them, each with an almost imperceptible effect.
Researchers therefore combed through almost the entire genome of nearly 5,000 volunteers in search of tiny changes, called polymorphisms, that correspond to variations in height. Eventually they found a single-letter DNA substitution, buried in a gene called HMGA2, that influences height.
People with two copies of the 'tall' variant of HMGA2 are, on average, almost a centimetre taller than those with two copies of the 'short' version. Those with one copy of each are somewhere in the middle. Follow-up testing of some 29,000 people confirmed that HMGA2 does indeed affect height, the research group reports in Nature Genetics1.
The height of medicine
"It doesn't explain why one person is six foot five and another is four foot ten — in terms of the variation it is about 1%," explains Timothy Frayling of Peninsula Medical School in Exeter, UK, who led the international research consortium. "But there are possibly several hundred more polymorphisms that also influence height."
It's also not exactly clear how HMGA2 influences height, despite the fact that rare severe mutations in the gene are already known to alter body size in both mice and humans. The gene is involved in unravelling the protein-rich structure, called chromatin, in which chromosomes are packaged, leading Frayling to speculate that the gene may influence the speed at which DNA is replicated during cell division, thus affecting overall body growth.
Nevertheless, simply knowing which genes help to determine height could help doctors decide whether small kids have naturally 'short' genes, or whether they are suffering from a medical condition that stunts growth. "For a lot of children who perhaps are a bit behind their growth chart, there is a pressure for doctors to treat them or find something wrong with them," Frayling says. "If we can find 50 or 100 height genes, we could look at them and say 'this is entirely in keeping with your height profile'."
Short on evidence
The discovery could also help to piece together the genetic framework of diseases such as diabetes and cancer, suggests another member of the research group, Joel Hirschhorn of the MIT Broad Institute and the Children's Hospital, both in Boston, Massachusetts.
There is some evidence that slightly shorter-than-average people are susceptible to diabetes, although this may be for socio-economic reasons. Conversely, taller people tend to be more prone to cancer, perhaps because they simply have more growing cells in which the disease can arise.
Discovering the genes that govern height would allow geneticists to examine whether different versions of these genes are linked to increased rates of various diseases, and could even help them work out the mechanisms involved.
In the meantime, however, Frayling and his colleagues are searching for yet more genes that influence height. "We won't expose all of the genetic basis of height, but over the next couple of years, we might find several hundred [genes] — perhaps 50% of the variation," Frayling says.
In theory, it's simply a question of getting DNA samples from as many people as possible, so that the tiny statistical effects of individual genes can be teased out. "Unlike most other complex traits, height is something that can be easily defined and measured in very large numbers of people," Hirschhorn says.
It doesn't explain why one person is six foot five and another is four foot ten - in terms of the variation it is about 1%.
Peninsula Medical School, Exeter