The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

M. Mei-Zahav; P. Stafler; H. Senderowitz; L. Bentur; G. Livnat; M. Shteinberg; N. Orenstein; L. Bazak; D. Prais; H. Levine; M. Gur; N. Khazanov; L. Simhaev; H. Eliyahu; M. Cohen; M. Wilschanski; H. Blau; H. Mussaffi

doi:10.1016/j.jcf.2018.06.008

The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

M. Mei-Zahav, P. Stafler, H. Senderowitz, L. Bentur, G. Livnat, M. Shteinberg, N. Orenstein, L. Bazak, D. Prais, H. Levine, M. Gur, N. Khazanov, L. Simhaev, H. Eliyahu, M. Cohen, M. Wilschanski, H. Blau, H. Mussaffi

Department of Chemistry

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2 Scopus citations

Abstract

Background: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. Methods: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. Results: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25–38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV₁ was 88 (40–121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1–14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. Conclusion: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

Original language	English
Pages (from-to)	e41-e45
Journal	Journal of Cystic Fibrosis
Volume	17
Issue number	5
DOIs	https://doi.org/10.1016/j.jcf.2018.06.008
State	Published - Sep 2018

Bibliographical note

Funding Information:
This work was supported by the Cystic Fibrosis Foundation Therapeutics, grant SENDER13XX0.

Publisher Copyright:
© 2018 European Cystic Fibrosis Society

Keywords

Georgian Jews
Q359K/T360K mutation
Structural models of CFTR

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10.1016/j.jcf.2018.06.008

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Mei-Zahav, M., Stafler, P., Senderowitz, H., Bentur, L., Livnat, G., Shteinberg, M., Orenstein, N., Bazak, L., Prais, D., Levine, H., Gur, M., Khazanov, N., Simhaev, L., Eliyahu, H., Cohen, M., Wilschanski, M., Blau, H., & Mussaffi, H. (2018). The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews. Journal of Cystic Fibrosis, 17(5), e41-e45. https://doi.org/10.1016/j.jcf.2018.06.008

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title = "The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews",

abstract = "Background: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. Methods: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. Results: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25–38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40–121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1–14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. Conclusion: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.",

keywords = "Georgian Jews, Q359K/T360K mutation, Structural models of CFTR",

author = "M. Mei-Zahav and P. Stafler and H. Senderowitz and L. Bentur and G. Livnat and M. Shteinberg and N. Orenstein and L. Bazak and D. Prais and H. Levine and M. Gur and N. Khazanov and L. Simhaev and H. Eliyahu and M. Cohen and M. Wilschanski and H. Blau and H. Mussaffi",

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year = "2018",

month = sep,

doi = "10.1016/j.jcf.2018.06.008",

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Mei-Zahav, M, Stafler, P, Senderowitz, H, Bentur, L, Livnat, G, Shteinberg, M, Orenstein, N, Bazak, L, Prais, D, Levine, H, Gur, M, Khazanov, N, Simhaev, L, Eliyahu, H, Cohen, M, Wilschanski, M, Blau, H & Mussaffi, H 2018, 'The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews', Journal of Cystic Fibrosis, vol. 17, no. 5, pp. e41-e45. https://doi.org/10.1016/j.jcf.2018.06.008

TY - JOUR

T1 - The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

AU - Mei-Zahav, M.

AU - Stafler, P.

AU - Senderowitz, H.

AU - Bentur, L.

AU - Livnat, G.

AU - Shteinberg, M.

AU - Orenstein, N.

AU - Bazak, L.

AU - Prais, D.

AU - Levine, H.

AU - Gur, M.

AU - Khazanov, N.

AU - Simhaev, L.

AU - Eliyahu, H.

AU - Cohen, M.

AU - Wilschanski, M.

AU - Blau, H.

AU - Mussaffi, H.

PY - 2018/9

Y1 - 2018/9

N2 - Background: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. Methods: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. Results: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25–38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40–121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1–14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. Conclusion: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

AB - Background: The Q359K/T360K mutation, described in Jewish CF patients of Georgian decent, is of questionable clinical significance. Methods: Clinical records of patients with the Q359K/T360K mutation from three CF centers were studied for phenotypic expression and putative mechanism of dysfunction. Computer models of mutant CFTR were constructed. Results: Nine patients (4 homozygous) of Georgian Jewish origin were included. Age at diagnosis was 9.4 (0.25–38.2) years, median (range). Sweat chloride was 106 ± 13 meq/L, mean ± SD. Nasal Potential Difference performed in three, was abnormal. All had pulmonary symptoms since early childhood and bronchiectasis. Median FEV1 was 88 (40–121)%. Five had chronic mucoid P. aeruginosa. Homozygous patients were pancreatic insufficient. Enzyme supplementation was initiated at 3.8 (1–14.7) years, median (range). Structural models hint at possible interference of this mutation with transmembrane chloride transport. Conclusion: In our cohort, the Q359K/T360K mutation resulted in a severe CF phenotype, although with residual early CFTR function. The CFTR2 database should consider defining this mutation as CF-causing.

KW - Georgian Jews

KW - Q359K/T360K mutation

KW - Structural models of CFTR

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U2 - 10.1016/j.jcf.2018.06.008

DO - 10.1016/j.jcf.2018.06.008

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C2 - 30033373

SN - 1569-1993

VL - 17

SP - e41-e45

JO - Journal of Cystic Fibrosis

JF - Journal of Cystic Fibrosis

IS - 5

ER -

The Q359K/T360K mutation causes cystic fibrosis in Georgian Jews

Abstract

Bibliographical note

Keywords

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