De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

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Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

eLife ◽

10.7554/elife.06315 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 148

Author(s):

Ute I Scholl ◽

Gabriel Stölting ◽

Carol Nelson-Williams ◽

Alfred A Vichot ◽

Murim Choi ◽

...

Keyword(s):

Calcium Channel ◽

Primary Aldosteronism ◽

Early Onset ◽

De Novo ◽

Incomplete Penetrance ◽

De Novo Mutations ◽

Channel Inactivation ◽

Aldosterone Production ◽

Genome Level ◽

Insight Into

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension.

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Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine

European Journal of Human Genetics ◽

10.1038/sj.ejhg.5201607 ◽

2006 ◽

Vol 14 (5) ◽

pp. 555-560 ◽

Cited By ~ 45

Author(s):

Kaate R J Vanmolkot ◽

Esther E Kors ◽

Ulku Turk ◽

Dylsad Turkdogan ◽

Antoine Keyser ◽

...

Keyword(s):

De Novo ◽

Familial Hemiplegic Migraine ◽

De Novo Mutations ◽

Hemiplegic Migraine ◽

Atpase Gene

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De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction

Diabetes ◽

10.2337/db19-1029 ◽

2019 ◽

Vol 69 (3) ◽

pp. 477-483 ◽

Cited By ~ 2

Author(s):

Elisa De Franco ◽

Richard Caswell ◽

Matthew B. Johnson ◽

Matthew N. Wakeling ◽

Amnon Zung ◽

...

Keyword(s):

Early Onset ◽

Hepatic Dysfunction ◽

De Novo ◽

De Novo Mutations ◽

Onset Diabetes

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De Novo Mutations (GAG Deletion) in the DYT1 Gene in Two Non-Jewish Patients with Early-onset Dystonia

Human Molecular Genetics ◽

10.1093/hmg/7.7.1133 ◽

1998 ◽

Vol 7 (7) ◽

pp. 1133-1136 ◽

Cited By ~ 45

Author(s):

C. Klein ◽

M. F. Brin ◽

D. de Leon ◽

S. A. Limborska ◽

I. A. Ivanova-Smolenskaya ◽

...

Keyword(s):

Early Onset ◽

De Novo ◽

De Novo Mutations ◽

Dyt1 Gene

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A de novo deletional germline mutation in the MLH1 gene resulting in early onset colorectal cancer in a woman with a negative family history: A case report

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21067 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21067-21067

Author(s):

D. Zakalik ◽

N. S. Goldstein ◽

W. L. Ducaine

Keyword(s):

Colorectal Cancer ◽

Family History ◽

Early Onset ◽

De Novo ◽

Germline Mutations ◽

De Novo Mutations ◽

Mlh1 Gene ◽

Negative Family History ◽

Mmr Genes ◽

Early Onset Colorectal Cancer

21067 Background: Hereditary non-polyposis colorectal cancer (HNPCC) is a genetic disorder that results in an increased risk of early onset colorectal cancer (CRC). HNPCC is caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1 and MSH2, and is transmitted in an autosomal dominant manner. De novo germline mutations in MMR genes are exceedingly rare. We now describe a case of a de novo germline mutation in MLH1 associated with early onset CRC in a young woman with a negative family history. Methods: We present a case of a 31-year-old Caucasian female who presented with abdominal pain. Colonoscopy revealed a moderately differentiated adenocarcinoma with focal mucin production involving the sigmoid colon, with a final staging of T4N0M0. Genetic testing was offered because of her young age at diagnosis, having fulfilled the Bethesda guidelines. Microsatellite instability (MSI) testing using a panel of six microsatellite loci was performed on the tumor sample from the affected patient. Immunohistochemistry (IHC) testing for MLH1 and MSH2 was performed. Following counseling and with informed consent, DNA was isolated and sequenced using bi-directional PCR of the MLH1 gene. All exons of MLH1 and MSH2 were analyzed by standard Southern blot methods. Paternity was established using eight genetic loci. Results: The patient's tumor revealed high MSI and complete absence of MLH1 immunoreactivity. MSH2 IHC staining was normal. A large deletional mutation involving exons 5–12 of MLH1 was identified by Southern blot analysis. The patient's parents and siblings were tested and found to have wild type MLH1. Paternity was confirmed with greater than 99.9% certainty. Conclusions: De novo mutations in MMR genes are a rare cause of HNPCC. We report the first case of a large de novo deletion in the MLH1 gene accounting for early onset CRC. Such de novo mutations, albeit rare, must be considered in patients who present with early onset CRC and a negative family history. These results support the use of the Bethesda guidelines to identify individuals who may carry mutations in the MMR genes. No significant financial relationships to disclose.

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