Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

Angela J Lee; Karra A Jones; Russell J Butterfield; Mary O Cox; Chamindra G Konersman; Carla Grosmann; Jose E Abdenur; Monica Boyer; Brent Beson; Ching Wang; James J Dowling; Melissa A Gibbons; Alison Ballard; Joanne S Janas; Robert T Leshner; Sandra Donkervoort; Carsten G Bönnemann; Denise M Malicki; Robert B Weiss; Katherine D Mathews; Steven A Moore

doi:10.1212/NXG.0000000000000315

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Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

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Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G

Angela J Lee, Karra A Jones, Russell J Butterfield, Mary O Cox, Chamindra G Konersman, Carla Grosmann, Jose E Abdenur, Monica Boyer, Brent Beson, Ching Wang, …

Neurology. Genetics, Vol.5(2), pp.e315-e315

04/2019

DOI: 10.1212/NXG.0000000000000315

PMCID: PMC6454397

PMID: 31041397

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Abstract

To characterize the clinical phenotype, genetic origin, and muscle pathology of patients with the c.1387A>G mutation. Standardized clinical data were collected for all patients known to the authors with c.1387A>G mutations in . Muscle biopsies were reviewed and used for histopathology, immunostaining, Western blotting, and DNA extraction. Genetic analysis was performed on extracted DNA. We report the clinical phenotypes of 6 patients homozygous for the c.1387A>G mutation in . Onset of symptoms was <2 years, and 5 of the 6 patients never learned to walk. Brain MRIs were normal. Cognition was normal to mildly impaired. Microarray analysis of 5 homozygous c.1387A>G patients revealed a 500-kb region of shared homozygosity at 19q13.32, including . All 4 muscle biopsies available for review showed end-stage dystrophic pathology, near absence of glycosylated α-dystroglycan (α-DG) by immunofluorescence, and reduced molecular weight of α-DG compared with controls and patients with homozygous c.826C>A limb-girdle muscular dystrophy. The clinical features and muscle pathology in these newly reported patients homozygous for c.1387A>G confirm that this mutation causes congenital muscular dystrophy. The clinical severity might be explained by the greater reduction in α-DG glycosylation compared with that seen with the c.826C>A mutation. The shared region of homozygosity at 19q13.32 indicates that c.1387A>G is a founder mutation with an estimated age of 60 generations (∼1,200-1,500 years).

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Title: Subtitle: Clinical, genetic, and pathologic characterization of FKRP Mexican founder mutation c.1387A>G
Creators: Angela J Lee - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Karra A Jones - University of Iowa, Pathology
Russell J Butterfield - University of Utah
Mary O Cox - University of Iowa, Pathology
Chamindra G Konersman - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Carla Grosmann - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Jose E Abdenur - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Monica Boyer - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Brent Beson - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Ching Wang - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
James J Dowling - University of Toronto
Melissa A Gibbons - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Alison Ballard - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Joanne S Janas - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Robert T Leshner - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Sandra Donkervoort - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Carsten G Bönnemann - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Denise M Malicki - University of Iowa (A.J.L.), Carver College of Medicine; Department of Pathology (K.A.J., M.O.C., S.A.M.), University of Iowa; Departments of Pediatrics and Neurology (R.J.B.), University of Utah; Department of Neurology (C.G.K.), University of California San Diego; Department of Neurology (C.G.), Gillette Children's Specialty Healthcare; Division of Metabolic Disorders (J.E.A., M.B.), CHOC Children's; Department of Neurology (B.B.), Integris Southwest Medical Center; Departments of Pediatrics and Neurology (C.W.), Driscoll Children's Hospital; Departments of Paediatrics and Molecular Genetics (J.J.D.), Hospital for Sick Children, University of Toronto; Departments of Pediatrics and Neurology (M.A.G., J.S.J.), University of Colorado; Department of Physical Medicine and Rehabilitation (A.B.), University of Colorado; Department of Neurosciences (R.T.L.), University of California San Diego; National Institutes of Health (S.D., C.G.B.), Institute of Neurological Disorders and Stroke; Department of Pathology (D.M.M.), University of California San Diego; Department of Human Genetics (R.B.W.), University of Utah; and Departments of Pediatrics and Neurology (K.D.M.), University of Iowa
Robert B Weiss - University of Utah Hospital
Katherine D Mathews - University of Iowa, Stead Family Department of Pediatrics
Steven A Moore - University of Iowa, Pathology
Resource Type: Journal article
Publication Details: Neurology. Genetics, Vol.5(2), pp.e315-e315
DOI: 10.1212/NXG.0000000000000315
PMID: 31041397
PMCID: PMC6454397
NLM abbreviation: Neurol Genet
ISSN: 2376-7839
eISSN: 2376-7839
Grant note: UM1 HG008900 / NHGRI NIH HHS
Language: English
Date published: 04/2019
Academic Unit: Neurology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984070486502771

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