Download + n° 6 - Octubre 2007

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
<[email protected]> y José E. Dipierri <[email protected]>
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 shortstature 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
Arm span/height ratio (cociente brazada/talla)
96.5%
Sitting height/height ratio (talla sentado/total)
55.5%
Body–mass index
(Indice Masa Corporal)
P 50
Cubitus valgus
Yes
Short forearm
(antebrazo corto)
Yes
Bowing of forearm (antebrazo incurvado)
Yes
Appearance of muscular hypertrophy
Yes
Dislocation of ulna (at elbow)(luxac.cúbito en codo)Yes
Total
Score points
2
2
4
2
3
3
3
5
24
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 homeoboxcontaining 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 genotypephenotype 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; [email protected]
J Med Genet 2007;44:306–313
C:\Eudora\Dipi\attach\Rappold-Genotypes-phenotypes-children-short stature...JMG,07.pdf;
---------------------------------------------------------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
general population
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..
C:\Eudora\Dipi\attach\HMGA2_Nature_Genetics_Final.pdf;
News: First 'tall gene' found. Genetic variant can add nearly a centimetre to your stature.
Michael Hopkin
Nature, 2 September, 2007.
NEWS
Published online: 2 September 2007; | doi:10.1038/news070827-8
First 'tall gene' found
Genetic variant can add nearly a centimetre to your
stature.
Michael Hopkin
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.
Measuring up: height is influenced
by hundreds of different genes.
Researchers therefore combed
Image Source
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
Timothy Frayling
Peninsula Medical School,
chromosomes are packaged, leading
Exeter
Frayling to speculate that the gene
may influence the speed at which
DNA is replicated during cell division,
thus affecting overall body growth.
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%.
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.