Download + n° 1 - Mayo 2007

NOTICIERO GENETICO SEGEHU - Nº 1/2007
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/o Humana.
El mantenimiento y la difusión del mismo estarán a cargo de los colegas Martín
Roubicek < roubicek@mdp.edu.ar> y José E. Dipierri <dipierri@inbial.unju.edu.ar>
Sin embargo, se invita a todos los colegas a enviar sus contribuciones adjuntando un
pequeño comentario de la novedad y el PDF o documento correspondiente.
Se encuentran, a pedido de los interesados, los PDF de los articulos o documentos
completos disponibles, que se pueden solicitar al Dr. Roubicek.
Contenido:
Más omas: El Proyecto Varioma. Editorial. Nature Genetics 2007;39:423
Dupla dup/del: Sindrome de Potocki-Lupski/Síndrome de Smith-Magenis.
Am J Hum Genet 2007;80:633-49
Recesividad para Stickler. Am. J. Hum. Genet. 2006;79:449–457
Un solo gen/2 sindromes (Fuhrmann/Al-Awadi-Raas-Rothschild-Schinzel
Focomelia) Am. J. Hum. Genet. 2006;79:402–408
Más omas: El Proyecto Varioma
Con el Proyecto Varioma se pretende establecer, a través de la cooperación
internacional, un catálogo enciclopédico de las secuencias variantes que se
indexarían a las secuencias oficiales del genoma humano. Los países no ricos
o periféricos por fin podrían así participar del Proyecto Genoma Humano.
Editorial
What is the Human Variome Project?
Nature Genetics - 39, 423 (2007)
NOTA: Más detalles sobre este tema en el Noticiero Genético Nº 2
Dupla dup/del: Sindrome de Potocki-Lupski/Síndrome de SmithMagenis
El sindrome de Potocki-Lupski recientemente descrito se debe a la microduplicación
(17)(p11.2p11.2), la misma región de la microdeletion (17)(p11.2p11.2) del Sindrome
Smith-Magenis. Los rasgos clínicos de los pacientes con la microduplicación
(17)(p11.2p11.2) son distintos de aquellos observados en el Síndrome de SmithMagenis y los mismos incluyen: hipotonía, retardo mental apnea de sueño, anomalías
cardiovasculares y autismo.
Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2))
and Delineation of a Dosage-Sensitive Critical Interval That Can
Convey an Autism Phenotype
Lorraine Potocki, * Weimin Bi, * Diane Treadwell-Deering, Claudia M. B. Carvalho, Anna
Eifert, Ellen M. Friedman, Daniel Glaze, Kevin Krull, Jennifer A. Lee, Richard Alan Lewis,
Roberto Mendoza-Londono, Patricia Robbins-Furman, Chad Shaw, Xin Shi, George
Weissenberger, Marjorie Withers, Svetlana A. Yatsenko, Elaine H. Zackai, Pawel Stankiewicz,
and James R. Lupski
From the Departments of Molecular and Human Genetics (L.P.; W.B.; C.M.B.C.; J.A.L.; R.A.L.; P.R.-F.;
C.S.; X.S.; G.W.; M.W.; S.A.Y.; P.S.; J.R.L.), Psychiatry and Behavioral Sciences (D.T.-D.), Speech
Language and Learning (A.E.), Otolaryngology (E.M.F.), Neurology (D.G.), Ophthalmology (R.A.L.),
Pediatrics (K.K.; R.A.L.; J.R.L.), and Allied Health (K.K.), Baylor College of Medicine, and Texas
Children’s Hospital (L.P.; D.T.-D.; A.E.; E.M.F.; D.G.; K.K.; J.R.L.), Houston; Department of
Paediatrics, Division of Clinical and Metabolic Genetics, University of Toronto, Toronto (R.M.-L.); and
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (E.H.Z.)
Address for correspondence and reprints: Dr. James R. Lupski, Department of Molecular and Human
Genetics, Baylor College of Medicine, Room 604B, One Baylor Plaza, Houston, TX 77030-3498.
E-mail: jlupski@bcm.tmc.edu
Am. J. Hum. Genet. 2007;80(4):633–649.
The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently
recognized syndrome of multiple congenital anomalies and mental retardation and is the
first predicted reciprocal microduplication syndrome described— the homologous
recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)
(p11.2p11.2)).We previously described seven subjects with dup(17)(p11.2p11.2) and
noted their relatively mild phenotype compared with that of individuals with SMS.
Here, we molecularly analyzed 28 additional patients, using multiple independent
assays, and also report the phenotypic characteristics obtained from extensive
multidisciplinary clinical study of a subset of these patients. Whereas the majority of
subjects (22 of 35) harbor the homologous recombination reciprocal product of the
common SMS microdeletion ( ¡« 3.7 Mb), 13 subjects ( ¡« 37%) have nonrecurrent
duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential
mechanistic differences between nonrecurrent duplications and nonrecurrent genomic
deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2)
are distinct from those seen with SMS and include infantile hypotonia, failure to thrive,
mental retardation, autistic features, sleep apnea, and structural cardiovascular
anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the
dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski
syndrome, provide information to assist in clinical diagnosis and management, and lend
further support for the concept that genomic architecture incites genomic instability.
Recesividad para Stickler
Este artículo aporta una alternativa importante al asesoramiento habitual del
síndrome de Stickler, ya que a los genes habitualmente implicados en familias
con transmisión del tipo autosómico dominante, habrá que agregar la
posibilidad de una forma autosómica recesiva, como en esta familia
consanguínea de origen marroquí, y el gen de colágeno COL 9A1 a los ya
conocidos COL2A1, COL11A1, and COL11A2. Como lo indica el trabajo, esto
modifica nuestra idea sobre la fisiopatología del colágeno y tendrá un impacto
profundo sobre el asesoramiento genético de este síndrome. En el catálogo
McKusick (OMIM) el gen figura bajo el número 120210 y relacionado con una
forma de la displasia epifisaria múltiple. Evidentemente, otras mutaciones del
mismo gen pueden ocasionar un síndrome esquelético bastante diferente.
A New Autosomal Recessive Form of Stickler Syndrome Is Caused by
a Mutation in the COL9A1 Gene
Guy Van Camp, Rikkert L. Snoeckx,* Nele Hilgert, Jenneke van den Ende, Hisakumi Fukuoka,
Michio Wagatsuma, Hiroaki Suzuki, R. M. Erica Smets, Filip Vanhoenacker, Frank Declau,
Paul Van De Heyning, and Shin-ichi Usami.
From the Department of Medical Genetics, University of Antwerp (G.V.C.; R.L.S.; N.H.; J.v.d.E.), and
Departments of Ophthalmology (R.M.E.S.), Radiology (F.V.), and Otorhinolaryngology, Head & Neck
Surgery and Communication Disorders (F.D.; P.V.D.H.), Antwerp University Hospital, Antwerp,
Belgium; and Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto,
Japan (H.F.; M.W.; H.S.; S.-i.U.)
Address for correspondence and reprints: Dr. Guy Van Camp, Department of Medical Genetics,
University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium. E-mail address:
guy.vancamp@ua.ac.be * Present affiliation: Stem Cell Institute, University of Leuven, Leuven, Belgium.
Am. J. Hum. Genet. 2006;79:449–457
Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory
manifestations. It has an autosomal dominant inheritance pattern and is caused by
mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan
origin that consists of four children with Stickler syndrome, six unaffected children, and
two unaffected parents who are distant relatives (fifth degree). All family members were
clinically investigated for ear, nose, and throat; ophthalmologic; and radiological
abnormalities. Four children showed symptoms characteristic of Stickler syndrome,
including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with
vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located
on chromosome 6q13, to be a candidate gene on the basis of the structural association
with collagen types II and XI and because of the high expression in the human inner ear
indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1
gene showed a homozygous R295X mutation in the four affected children. The parents
and four unaffected children were heterozygous carriers of the R295X mutation. Two
unaffected children were homozygous for the wild-type allele. None of the family
members except the homozygous R295X carriers had any signs of Stickler syndrome.
Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In
contrast to the three previously reported Stickler syndrome–causing genes, this gene
causes a form of Stickler syndrome with an autosomal recessive inheritance pattern.
This finding will have a major impact on the genetic counseling of patients with Stickler
syndrome and on the understanding of the pathophysiology of collagens. Mutation
analysis of this gene is recommended in patients with Stickler syndrome with possible
autosomal recessive inheritance.
Un solo gen/2 sindromes (Fuhrmann/Al-Awadi-Raas-RothschildSchinzel Focomelia)
Interesante trabajo que relaciona 2 síndromes bien caracterizados como
alélicos según se trata de una deficiencia parcial o total (mutación nula) del
mismo gen WNT7A implicado en el desarrollo dorsoventral del esbozo de
miembros. Poco a poco se van identificando los variados genes que intervienen
en la formación de los miembros de los vertebrados. Los autores de este
trabajo L.Al-Gazali y Stefan Mundlos son investigadores conocidos en estos
temas; el último fue originalmente colaborador en el equipo del Prof. Jürgen
Spranger en Mainz, Alemania. Un artículo general sobre el tema de formación
de los miembros de vertebrados apareció en un número especial de Nature,
junto con otros temas de biología del esqueleto (Mariani y Martin, 2003). Sin
embargo, en ese artículo el gen WNT aparece apenas mencionado. En el
catálogo OMIM figura como:*601570 WINGLESS-TYPE MMTV INTEGRATION
SITE FAMILY, MEMBER 7A; WNT7A. El gen WNT7A no solo guía el desarrollo
del eje anteroposterior del tracto reproductivo femenino sino que también juega
un rol crítico en la conformación del músculo liso uterino y el mantenimiento de
la función uterina adulta. También es responsable de los cambios de niveles de
la hormona esteroide humana en el tracto resproductivo femenino.
Mutations in WNT7A Cause a Range of Limb Malformations,
Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/
Schinzel Phocomelia Syndrome
C. G. Woods,* S. Stricker,* P. Seemann, R. Stern, J. Cox, E. Sherridan, E. Roberts, K.
Springell, S. Scott, G. Karbani, S. M. Sharif, C. Toomes, J. Bond, D. Kumar, L. Al-Gazali, and
S. Mundlos
From the Department of Medical Genetics, Cambridge Institute for Medical Research, University of
Cambridge, Cambridge, United Kingdom (C.G.W.; R.S.; J.C.); Max-Planck Institute for Molecular
Genetics and Institute for Medical Genetics, Charite´, Berlin (S. Stricker; P.S.; S.M.); Department of
Clinical Genetics (E.S.; G.K.; S.M.S.) and Section of Ophthalmology and Neuroscience, Leeds Institute
of Molecular Medicine (E.R.; K.S.; S. Scott; C.T.; J.B.), St James’s University Hospital, Leeds, United
Kingdom; Centre for Human Genetics, Sheffield Children’s Hospital, Sheffield, United Kingdom (D.K.);
and Department of Paediatrics, Faculty of Medicine and Health Sciences, United Arab Emirates
University, Al-Anin, United Arab Emirates (L.A.-G.).Address for correspondence and reprints: Dr. C. G.
Woods, Department of Medical Genetics, Cambridge Institute for Medical Research, University of
Cambridge, Hills Road, Cambridge CB2 2XY, United Kingdom. E-mail: cw347@cam.ac.uk
Am. J. Hum. Genet. 2006;79:402–408
Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome
are considered to be distinct limb-malformation disorders characterized by various
degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these
syndromes, we found homozygous missense mutations in the dorsovental-patterning
geneWNT7A and confirmed their functional significance in retroviral-mediated
transfection of chicken mesenchyme cell cultures and developing limbs. The results
suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a
phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation
phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome
result from null mutations (and cause a phenotype similar to mouse Shh knockout).
These findings illustrate the specific and conserved importance of WNT7A in multiple
aspects of vertebrate limb development.