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Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").

Pachlopnik Schmid J, Lemoine R, Nehme N, Cormier-Daire V, Revy P, Debeurme F, Debré M, Nitschke P, Bole-Feysot C, Legeai-Mallet L, Lim A, de Villartay JP, Picard C, Durandy A, Fischer A, de Saint Basile G - J. Exp. Med. (2012)

Bottom Line: Its primary function is to synthesize DNA at the leading strand during replication.The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit.Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Institute of Health and Medical Research (INSERM) Unit 768, Paris, France.

ABSTRACT
DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

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Pedigree and clinical manifestations in patients with the FILS phenotype. (A) Pedigree of the family with FILS. Family members having provided DNA are numbered. Completely closed symbols indicate affected individuals, and half closed symbols indicate a heterozygous carrier. An arrow designates the index case. Individuals clustered in a diamond symbol in generation IV and V were not analyzed. Gray symbols indicate patients that did not undergo genetic testing. Slashes indicate deceased persons, double horizontal lines consanguinity, and dotted lines presumed interrelations. Case J* died after a pulmonary infection at the age of 2 yr. (B) Facial profile photographs showing patient VI-36 at the age of 9, with livedo on the cheek and discrete malar hypoplasia (left), telangiectasia on the cheek of patient VI-11 at the age of 33 (middle) and, lastly, livedo on the thigh of patient VI-11 (right). (C) Growth charts for male (left) and female (right) patients, showing short stature in all instances and particularly substantial growth impairment in patients VI-3, VI-10, VI-11, VI-12, VI-28, and VII-1. (D) X ray of the forearm of case VI-3 (left) and patient VI-29 (middle) showing irregular diaphyseal hyperostosis (arrows) and x-ray of the leg of patient VI-29 (right) showing irregular diaphyseal hyperostosis and metaphyseal striations (arrow). (E) IgM levels in patients (closed dots) and heterozygous individuals (open dots) of different ages. The shaded area indicates our in-house normative values. (F) Percentages of memory B cells (CD27+/CD19+) in patients (closed dots). The shaded area indicates normal level from in-house control values.
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fig1: Pedigree and clinical manifestations in patients with the FILS phenotype. (A) Pedigree of the family with FILS. Family members having provided DNA are numbered. Completely closed symbols indicate affected individuals, and half closed symbols indicate a heterozygous carrier. An arrow designates the index case. Individuals clustered in a diamond symbol in generation IV and V were not analyzed. Gray symbols indicate patients that did not undergo genetic testing. Slashes indicate deceased persons, double horizontal lines consanguinity, and dotted lines presumed interrelations. Case J* died after a pulmonary infection at the age of 2 yr. (B) Facial profile photographs showing patient VI-36 at the age of 9, with livedo on the cheek and discrete malar hypoplasia (left), telangiectasia on the cheek of patient VI-11 at the age of 33 (middle) and, lastly, livedo on the thigh of patient VI-11 (right). (C) Growth charts for male (left) and female (right) patients, showing short stature in all instances and particularly substantial growth impairment in patients VI-3, VI-10, VI-11, VI-12, VI-28, and VII-1. (D) X ray of the forearm of case VI-3 (left) and patient VI-29 (middle) showing irregular diaphyseal hyperostosis (arrows) and x-ray of the leg of patient VI-29 (right) showing irregular diaphyseal hyperostosis and metaphyseal striations (arrow). (E) IgM levels in patients (closed dots) and heterozygous individuals (open dots) of different ages. The shaded area indicates our in-house normative values. (F) Percentages of memory B cells (CD27+/CD19+) in patients (closed dots). The shaded area indicates normal level from in-house control values.

Mentions: 11 members of a large, consanguineous French kindred displayed mild facial dysmorphism, immunodeficiency, livedo, and short stature (referred to by us as “FILS syndrome”). Three additional members displayed two or three of these four features. The pedigree and clinical features of the family members investigated in the present study are shown in Fig. 1, Table 1, and Table S1. One affected individual (VI-11) has four children and so the syndrome is not associated with (male) infertility (Fig. 1 A). The patients had mild facial dysmorphism with malar hypoplasia (Fig. 1 B) and a high forehead. Livedo on the cheeks, forearms, and/or legs was present in all but one patient and noticed since birth in numbers of them (Fig. 1 B). There was no ulceration. With increasing age, telangiectasia was observed on the cheeks. Patients were born at term with a normal gestational weight and length. Growth impairment was observed during early childhood and resulted in shortness of height in adulthood, though to varying degree (Fig. 1 C). The mean height of the unaffected siblings was around the 50th percentile. Growth hormone production and response were tested in three patients and found to be normal. The head circumference was normal in all but one patient (VI-3), and thus the FILS patients had a relative macrocephaly. Patients VI-3, VI-11, and VI-29 had bone dysplasia and suffered from pain in the extremities; lacunar bone lesions, cortical thickening, and modeling defects at the long bone diaphyses were found in the three patients, whereas striae in the metaphyses were observed in patient VI-3 only (Fig. 1 D).


Polymerase ε1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome").

Pachlopnik Schmid J, Lemoine R, Nehme N, Cormier-Daire V, Revy P, Debeurme F, Debré M, Nitschke P, Bole-Feysot C, Legeai-Mallet L, Lim A, de Villartay JP, Picard C, Durandy A, Fischer A, de Saint Basile G - J. Exp. Med. (2012)

Pedigree and clinical manifestations in patients with the FILS phenotype. (A) Pedigree of the family with FILS. Family members having provided DNA are numbered. Completely closed symbols indicate affected individuals, and half closed symbols indicate a heterozygous carrier. An arrow designates the index case. Individuals clustered in a diamond symbol in generation IV and V were not analyzed. Gray symbols indicate patients that did not undergo genetic testing. Slashes indicate deceased persons, double horizontal lines consanguinity, and dotted lines presumed interrelations. Case J* died after a pulmonary infection at the age of 2 yr. (B) Facial profile photographs showing patient VI-36 at the age of 9, with livedo on the cheek and discrete malar hypoplasia (left), telangiectasia on the cheek of patient VI-11 at the age of 33 (middle) and, lastly, livedo on the thigh of patient VI-11 (right). (C) Growth charts for male (left) and female (right) patients, showing short stature in all instances and particularly substantial growth impairment in patients VI-3, VI-10, VI-11, VI-12, VI-28, and VII-1. (D) X ray of the forearm of case VI-3 (left) and patient VI-29 (middle) showing irregular diaphyseal hyperostosis (arrows) and x-ray of the leg of patient VI-29 (right) showing irregular diaphyseal hyperostosis and metaphyseal striations (arrow). (E) IgM levels in patients (closed dots) and heterozygous individuals (open dots) of different ages. The shaded area indicates our in-house normative values. (F) Percentages of memory B cells (CD27+/CD19+) in patients (closed dots). The shaded area indicates normal level from in-house control values.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3526359&req=5

fig1: Pedigree and clinical manifestations in patients with the FILS phenotype. (A) Pedigree of the family with FILS. Family members having provided DNA are numbered. Completely closed symbols indicate affected individuals, and half closed symbols indicate a heterozygous carrier. An arrow designates the index case. Individuals clustered in a diamond symbol in generation IV and V were not analyzed. Gray symbols indicate patients that did not undergo genetic testing. Slashes indicate deceased persons, double horizontal lines consanguinity, and dotted lines presumed interrelations. Case J* died after a pulmonary infection at the age of 2 yr. (B) Facial profile photographs showing patient VI-36 at the age of 9, with livedo on the cheek and discrete malar hypoplasia (left), telangiectasia on the cheek of patient VI-11 at the age of 33 (middle) and, lastly, livedo on the thigh of patient VI-11 (right). (C) Growth charts for male (left) and female (right) patients, showing short stature in all instances and particularly substantial growth impairment in patients VI-3, VI-10, VI-11, VI-12, VI-28, and VII-1. (D) X ray of the forearm of case VI-3 (left) and patient VI-29 (middle) showing irregular diaphyseal hyperostosis (arrows) and x-ray of the leg of patient VI-29 (right) showing irregular diaphyseal hyperostosis and metaphyseal striations (arrow). (E) IgM levels in patients (closed dots) and heterozygous individuals (open dots) of different ages. The shaded area indicates our in-house normative values. (F) Percentages of memory B cells (CD27+/CD19+) in patients (closed dots). The shaded area indicates normal level from in-house control values.
Mentions: 11 members of a large, consanguineous French kindred displayed mild facial dysmorphism, immunodeficiency, livedo, and short stature (referred to by us as “FILS syndrome”). Three additional members displayed two or three of these four features. The pedigree and clinical features of the family members investigated in the present study are shown in Fig. 1, Table 1, and Table S1. One affected individual (VI-11) has four children and so the syndrome is not associated with (male) infertility (Fig. 1 A). The patients had mild facial dysmorphism with malar hypoplasia (Fig. 1 B) and a high forehead. Livedo on the cheeks, forearms, and/or legs was present in all but one patient and noticed since birth in numbers of them (Fig. 1 B). There was no ulceration. With increasing age, telangiectasia was observed on the cheeks. Patients were born at term with a normal gestational weight and length. Growth impairment was observed during early childhood and resulted in shortness of height in adulthood, though to varying degree (Fig. 1 C). The mean height of the unaffected siblings was around the 50th percentile. Growth hormone production and response were tested in three patients and found to be normal. The head circumference was normal in all but one patient (VI-3), and thus the FILS patients had a relative macrocephaly. Patients VI-3, VI-11, and VI-29 had bone dysplasia and suffered from pain in the extremities; lacunar bone lesions, cortical thickening, and modeling defects at the long bone diaphyses were found in the three patients, whereas striae in the metaphyses were observed in patient VI-3 only (Fig. 1 D).

Bottom Line: Its primary function is to synthesize DNA at the leading strand during replication.The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit.Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Institute of Health and Medical Research (INSERM) Unit 768, Paris, France.

ABSTRACT
DNA polymerase ε (Polε) is a large, four-subunit polymerase that is conserved throughout the eukaryotes. Its primary function is to synthesize DNA at the leading strand during replication. It is also involved in a wide variety of fundamental cellular processes, including cell cycle progression and DNA repair/recombination. Here, we report that a homozygous single base pair substitution in POLE1 (polymerase ε 1), encoding the catalytic subunit of Polε, caused facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome") in a large, consanguineous family. The mutation resulted in alternative splicing in the conserved region of intron 34, which strongly decreased protein expression of Polε1 and also to a lesser extent the Polε2 subunit. We observed impairment in proliferation and G1- to S-phase progression in patients' T lymphocytes. Polε1 depletion also impaired G1- to S-phase progression in B lymphocytes, chondrocytes, and osteoblasts. Our results evidence the developmental impact of a Polε catalytic subunit deficiency in humans and its causal relationship with a newly recognized, inherited disorder.

Show MeSH
Related in: MedlinePlus