<?xml version="1.0" encoding="ISO-8859-1"?><article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance">
<front>
<journal-meta>
<journal-id>1889-836X</journal-id>
<journal-title><![CDATA[Revista de Osteoporosis y Metabolismo Mineral]]></journal-title>
<abbrev-journal-title><![CDATA[Rev Osteoporos Metab Miner]]></abbrev-journal-title>
<issn>1889-836X</issn>
<publisher>
<publisher-name><![CDATA[Sociedad Española de Investigaciones Óseas y Metabolismo Mineral]]></publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id>S1889-836X2018000400002</article-id>
<article-id pub-id-type="doi">10.4321/s1889-836x2018000400002</article-id>
<title-group>
<article-title xml:lang="es"><![CDATA[Estudio genético de la fractura femoral atípica mediante la secuenciación del exoma en tres hermanas afectas y tres pacientes no relacionadas]]></article-title>
<article-title xml:lang="en"><![CDATA[Genetic study of atypical femoral fractures using exome sequencing in three affected sisters and three unrelated patients]]></article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Roca-Ayats]]></surname>
<given-names><![CDATA[N]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Falcó-Mascaró]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[García-Giralt]]></surname>
<given-names><![CDATA[N]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Cozar]]></surname>
<given-names><![CDATA[M]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Abril]]></surname>
<given-names><![CDATA[JF]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Quesada-Gómez]]></surname>
<given-names><![CDATA[JM]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Prieto-Alhambra]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
<xref ref-type="aff" rid="A a"/>
<xref ref-type="aff" rid="A06"/>
</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Nogués]]></surname>
<given-names><![CDATA[X]]></given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Mellibovsky]]></surname>
<given-names><![CDATA[L]]></given-names>
</name>
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</contrib>
<contrib contrib-type="author">
<name>
<surname><![CDATA[Díez-Pérez]]></surname>
<given-names><![CDATA[A]]></given-names>
</name>
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<contrib contrib-type="author">
<name>
<surname><![CDATA[Grinberg]]></surname>
<given-names><![CDATA[D]]></given-names>
</name>
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<contrib contrib-type="author">
<name>
<surname><![CDATA[Balcells]]></surname>
<given-names><![CDATA[S]]></given-names>
</name>
<xref ref-type="aff" rid="Aff"/>
</contrib>
</contrib-group>
<aff id="A01">
<institution><![CDATA[,Universidad de Barcelona Instituto de Biomedicina de la Universidad de Barcelona (IBUB) Instituto de Investigación Sant Joan de Déu (IRSJD)]]></institution>
<addr-line><![CDATA[Barcelona ]]></addr-line>
<country>España</country>
</aff>
<aff id="A02">
<institution><![CDATA[,Unidad de Investigación en Fisiopatología Ósea y Articular (URFOA) Instituto Hospital del Mar de Investigaciones Médicas (IMIM) Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES)]]></institution>
<addr-line><![CDATA[Barcelona ]]></addr-line>
<country>España</country>
</aff>
<aff id="A03">
<institution><![CDATA[,Universidad de Barcelona Departamento de Genética, Microbiología y Estadística Instituto de Biomedicina de la Universidad de Barcelona]]></institution>
<addr-line><![CDATA[Barcelona ]]></addr-line>
<country>España</country>
</aff>
<aff id="A04">
<institution><![CDATA[,Hospital Universitario Reina Sofía Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Salud Carlos III (ISCIII)]]></institution>
<addr-line><![CDATA[Córdoba ]]></addr-line>
<country>España</country>
</aff>
<aff id="A05">
<institution><![CDATA[,Universidad Autónoma de Barcelona (UAB) Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES) Instituto de Investigación en Atención Primaria (IDIAP)]]></institution>
<addr-line><![CDATA[Barcelona ]]></addr-line>
<country>España</country>
</aff>
<aff id="A06">
<institution><![CDATA[,Universidad de Oxford Departmento de Ortopedia, Reumatología y Ciencias Músculoesqueléticas Nuffield Instituto Nacional para la Investigación de la Salud]]></institution>
<addr-line><![CDATA[Oxford ]]></addr-line>
<country>Reino Unido</country>
</aff>
<pub-date pub-type="pub">
<day>00</day>
<month>12</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="epub">
<day>00</day>
<month>12</month>
<year>2018</year>
</pub-date>
<volume>10</volume>
<numero>4</numero>
<fpage>108</fpage>
<lpage>118</lpage>
<copyright-statement/>
<copyright-year/>
<self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_arttext&amp;pid=S1889-836X2018000400002&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_abstract&amp;pid=S1889-836X2018000400002&amp;lng=en&amp;nrm=iso"></self-uri><self-uri xlink:href="http://scielo.isciii.es/scielo.php?script=sci_pdf&amp;pid=S1889-836X2018000400002&amp;lng=en&amp;nrm=iso"></self-uri><abstract abstract-type="short" xml:lang="es"><p><![CDATA[Resumen  Objetivos: Las fracturas atípicas de fémur (FAF) son un tipo de fracturas poco frecuentes, a menudo relacionadas con un tratamiento prolongado con bisfosfonatos (BPs). Actualmente no se conocen con exactitud sus mecanismos patogénicos y no hay pruebas para identificar aquellos pacientes con un alto riesgo de sufrir una FAF. El objetivo de este trabajo es investigar las bases genéticas de las FAFs.  Material y métodos: Se secuenció el exoma completo de 3 hermanas y de 3 pacientes adicionales no relacionadas, todas tratadas con BPs durante más de 5 años. Se seleccionaron variantes compartidas por las hermanas, de baja frecuencia y potencialmente patogénicas, y se construyó una red de interacciones de genes y proteínas con los datos hallados.  Resultados: Identificamos 37 variantes raras (en 34 genes) compartidas por las 3 hermanas, algunas de ellas no descritas anteriormente. La variante más llamativa fue la mutación p.Asp188Tyr en el enzima geranilgeranil pirofosfato sintasa (codificada por el gen GGPS1), de la vía del mevalonato y esencial para la función del osteoclasto. Otro hallazgo interesante fueron dos mutaciones (una en las 3 hermanas y una en una paciente no relacionada) en el gen CYP1A1, implicado en el metabolismo de los esteroides. Identificamos otras variantes que también podrían estar involucradas en la susceptibilidad a las FAFs o en el fenotipo osteoporótico subyacente, tales como las presentes en los genes SYDE2, NGEF. COG4 y la FN1.  Conclusiones: Nuestros datos son compatibles con un modelo donde la acumulación de variantes de susceptibilidad podría participar en la base genética de las FAFs.]]></p></abstract>
<abstract abstract-type="short" xml:lang="en"><p><![CDATA[Abstract  Objectives: Atypical femoral fractures (AFF) are rare, often related to long-term bisphosphonate (BPs) treatment. Their pathogenic mechanisms are not precisely known and there is no evidence to identify patients with a high risk of AFF. The aim of this work is to study the genetic bases of AFFs.  Materials and methods: Whole-exome sequencing was carried out on 3 sisters and 3 unrelated additional patients, all treated with BPs for more than 5 years. Low frequency, potentially pathogenic variants shared by the 3 sisters, were selected, were selected and a network of gene and protein interactions was constructed with the data found.  Results: We identified 37 rare variants (in 34 genes) shared by the 3 sisters, some not previously described. The most striking variant was the p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase (encoded by the GGPS1 gene), from the mevalonate pathway and essential for osteoclast function. Another noteworthy finding was two mutations (one in the 3 sisters and one in an unrelated patient) in the CYP1A1 gene, involved in the metabolism of steroids. We identified other variants that could also be involved in the susceptibility to AFFs or in the underlying osteoporotic phenotype, such as those present in the SYDE2, NGEF, COG4 and FN1 genes.  Conclusions: Our data are compatible with a model where the accumulation of susceptibility variants could participate in the genetic basis of AFFs.]]></p></abstract>
<kwd-group>
<kwd lng="es"><![CDATA[fractura atípica de fèmur]]></kwd>
<kwd lng="es"><![CDATA[bisfosfonatos]]></kwd>
<kwd lng="es"><![CDATA[GGPS1]]></kwd>
<kwd lng="es"><![CDATA[CYP1A1]]></kwd>
<kwd lng="es"><![CDATA[secuenciación completa del exoma]]></kwd>
<kwd lng="en"><![CDATA[atypical femoral fractures]]></kwd>
<kwd lng="en"><![CDATA[bisphosphonates]]></kwd>
<kwd lng="en"><![CDATA[GGPS1]]></kwd>
<kwd lng="en"><![CDATA[CYP1A1]]></kwd>
<kwd lng="en"><![CDATA[whole-exome sequencing]]></kwd>
</kwd-group>
</article-meta>
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